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papers/1623898.md

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+# The effect of quinidine on the analgesic effect of codeine.
+
+S H Sindrup, L Arendt-Nielsen, K Brøsen, P Bjerring, H R Angelo, B Eriksen, L F Gram
+
+*European journal of clinical pharmacology* (1992)
+
+PMID: 1623898
+DOI: 10.1007/BF00265920
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+We have studied the hypoalgesic effect of codeine (100 mg) after blocking the hepatic O-demethylation of codeine to morphine via the sparteine oxygenase (CYP2D6) by quinidine (200 mg). The study was performed in 16 extensive metabolizers of sparteine, using a double-blind, randomized, four-way, cross-over design. The treatments given at 3 h intervals during the four sessions were placebo/placebo, quinidine/placebo, placebo/codeine, and quinidine/codeine. We measured pinprick pain and pain tolerance thresholds to high energy argon laser stimuli before and 1, 2, and 3 h after codeine or placebo. After codeine and placebo, the peak plasma concentration of morphine was 6-62 (median 18) nmol.l-1. When quinidine pre-treatment was given, no morphine could be detected (less than 4 nmol.l-1) after codeine. The pin-prick pain thresholds were significantly increased after placebo/codeine, but not after quinidine/codeine compared with placebo/placebo. Both placebo/codeine and quinidine/codeine increased pain tolerance thresholds significantly. Quinidine/codeine and quinidine/placebo did not differ significantly for either pin-prick or tolerance pain thresholds. These results are compatible with local CYP2D6 mediated formation of morphine in the brain, not being blocked by quinidine. Alternatively, a hypoalgesic effect of quinidine might have confounded the results.

papers/1623898.pdf

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papers/1623898.txt

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+Eur J Clin Pharmacol (1992) 42:587-592 
+European J .... Io, (~[~1~(~@~ 
+© Springer-Verlag 1992 
+The effect of quinidine on the analgesic effect of codeine 
+S. H. Sindrup I , L. Arendt-Nielsen 2, K. Brosen 1 , P. Bj erring 3 , H. R. Angelo 4, B. Eriksen 5 , and L. F. Gram s 
+Department of Cli~ical Pharmacology, Odense University, 2 Department of Medical Informatics, Aalborg University, 
+3 Department of Dermatology, Marselisborg Hospital, Aarhus, 4 Department of Clinical Chemistry, Bispebjerg Hospital, Copenhagen, and 
+5 DAK-Laboratoriet a/s, Copenhagen, Denmark 
+Received: October 8,1991/Accepted in revised form: January 23,1992 
+Summary. We have studied the hypoalgesic effect of 
+codeine (100 rag) after blocking the hepatic O-demethy- 
+lation of codeine to morphine via the sparteine oxygenase 
+(CYP2D6) by quinidine (200 mg). The study was per- 
+formed in 16 extensive metabolizers of sparteine, using a 
+double-blind, randomized, four-way, cross-over design. 
+The treatments given at 3 h intervals during the four ses- 
+sions were placebo/placebo, quinidine/placebo, place- 
+bo/codeine, and quinidine/codeine. We measured pin- 
+prick pain and pain tolerance thresholds to high energy 
+argon laser stimuli before and 1,2, and 3 h after codeine or 
+placebo. 
+After codeine and placebo, the peak plasma concentra- 
+tion of morphine was 6-62 (median 18) nmol. 1-1. When 
+quinidine pre-treatment was given, no morphine could be 
+detected ( < 4 nmol. 1-~) after codeine. The pin-prick pain 
+thresholds were significantly increased after placebo/co- 
+deine, but not after quinidine/codeine compared with 
+placebo/placebo. Both placebo/codeine and quinidine/co- 
+deine increased pain tolerance thresholds significantly. 
+Quinidine/codeine and quinidine/placebo did not differ 
+significantly for either pin-prick or tolerance pain thresh- 
+olds. 
+These results are compatible with local CYP2D6 medi- 
+ated formation of morphine in the brain, not being 
+blocked by quinidine. Alternatively, a hypoalgesic effect 
+of quinidine might have confounded the results. 
+Key words: Codeine, Quinidine; CYP2D6, hypoalgesia, 
+drug interaction 
+Codeine is eliminated primarily by glucuronidation. O- 
+demethylation to morphine and N-demethylation to nor- 
+codeine are minor pathways, each accounting for about 
+10 % of the dose [1] (Fig. 1). Forty years age it was sug- 
+gested that the hypoalgesic effect of codeine is mediated 
+by its metabolite morphine [2]. This view was supported 
+by subsequent experiments which showed that codeine 
+has much lower affinity for the ~t-opioid receptor than 
+morphine (less than 1/3000) [3]. Recently the role of mot- 
+phine has been questioned by the finding of very low plas- 
+ma concentrations of morphine after single and repeated 
+doses of codeine [4, 5]. However, the concentrations of the 
+potentially active metabolites of morphine, i.e. normor- 
+phine [6] and morphine-6-glucuronide [7], were not taken 
+into consideration. Furthermore, the plasma concentra- 
+tion may not reflect the concentration at the receptor site 
+in the target organ. In fact, it has been suggested that co- 
+deine acts through morphine formed locally in the brain 
+[8], but such local transformation has not yet been demon- 
+strated in humans. 
+Seven per cent of Caucasians are poor metabolizers of 
+sparteine/debrisoquine and the rest are extensive metabo- 
+lizers [9]. A particular P450, the CYP2D6 (or P450IID6), 
+is the source of this polymorphism, and in the poor me- 
+tabolizers this isozyme is absent from the liver [10]. It has 
+recently been shown that the O-demethylation of codeine 
+co-segregates with the sparteine/debrisoquine oxidation 
+polymorphism [11-14] and poor metabolizers are practi- 
+cally unable to metabolize codeine to morphine. In a re- 
+cent study we addressed the role of morphine in codeine 
+hypoalgesia. In 12 extensive and 12 poor metabolizers we 
+found that a single oral dose of 75 mg codeine increased 
+pin-prick pain thresholds to high energy laser stimuli in 
+the extensive but not in the poor metabolizers [15]. 
+Quinidine is a potent inhibitor of the CYP2D6 both in 
+vitro and in vivo [16--18] and the hepatic conversion of co- 
+deine to morphine in extensive metabolizers is practically 
+/__/"N - CH s 
+HO 
+CODEINE 
+6-glucuronidation ~ O-demethylation 
+~1 c-e-G t ................................... i 
+6-glucuronidation b [~ / O-demethylation ~ 3-glucuronidation 
+  ometh ,at,on 7 
+N-demethylation 6-glucuronidation~ 
+Fig.L The pattern of codeine metabolism in humans. Abbrevia- 
+tions: C-6-G = codeine-6-glucuronide, M = morphine, NC = nor- 
+codeine, M-6-G = morphine-6-glucuronide, M-3-G = morphine-3- 
+glucuronide, NM = normorphine, and NC-6-G = nor- 
+codeine-6-glucuronide 
+
+588 
+800- 
+700- 
+600- 
+500- 
+400- 
+-- 300- 
+200- 
+~, lO0- 
+g o 
+70- o 
+o 
+E 60- 
+~- 50- 
+40- 
+30- 
+20- 
+10- 
+4- 
+<4 
+Codeine 
+° i [] 
+[] [] 
+[] 
+$'-o .. 
+[] 
+B 
+Morphine 
+nn 
+•i 
+1 2 3 
+Time after dose (h) 
+Fig.2. The plasma concentrations of codeine and morphine 1, 2, and 
+3 h after 100 mg of codeine in 16 extensive metabolizers of sparteine 
+with ( [] ) and without ( • ) 200 mg quinidine pre-treatment 
+abolished after quinidine [19]. We have therefore studied 
+the effect of pre-treatment of 16 healthy extensive me- 
+tabolizers with 200 mg of quinidine on the hypoalgesia 
+produced by codeine. 
+Subjects and methods 
+Subjects 
+We studied 16 extensive metabolizers of sparteine (12 men and 
+4 women, aged 21-30 y, median 24) with a metabolic ratio (MR) be- 
+tween sparteine and dehydrosparteines of less than 1 in the 12 h 
+urine [20]. The volunteers were healthy and not regularly taking any 
+drugs (except two of the women who were taking oral contracep- 
+tives). Alcohol and additional analgesics were not allowed for 24 h 
+before and after the experiments. The study was approved by the re- 
+gional ethics committee and the subjects consented to participate on 
+the basis of verbal and written information. 
+Design and medication 
+The study was double-blind and randomized. We compared 100 mg 
+of codeine orally with placebo, and both drugs were given with and 
+without pre-treatment with a single oral dose of 200 mg quinidine in 
+a four-way cross-over design. The four different treatment sequence 
+combinations were thus: placebo/placebo, quinidine/placebo, place- 
+be/codeine, and quinidine/codeine. Codeine (25 rag, DAK-Labora- 
+toriet a/s, Copenhagen, Denmark) and codeine-placebo tablets were 
+of identical size and colour, as were the quinidine (200 mg, DAK- 
+Laboratoriet a/s, Copenhagen, Denmark) and quinidine-placebo 
+tablets. Four codeine or codeine-placebo tablets were given 3 h after 
+pre-treatment with one quinidine or quinidine-placebo tablet. The 
+study days were separated by at least two weeks for washout. The 
+pain threshold to laser stimulation was determined immediately be- 
+fore codeine or placebo (i. e. 3 h after quinidine Or the corresponding 
+placebo) and then 1,2, and 3 h after. 
+Laser stimulation and determination of pain thresholds 
+A detailed description of the method for determination of pain 
+thresholds to laser stimuli has previously been published [21]. Brief- 
+ly, the output (wavelenghts 488 and 515 nm) from an argon laser 
+(Model 168, Spectra Physics, USA) was transmitted to the skin 
+through a quartz fibre with a handpiece. The output power was ad- 
+justable from 50 mW to approximately 3 W and the energy which 
+reached the skin was measured by an external laser power meter 
+(Ophir, Israel). Laser stimuli of 200 ms duration and a beam 
+diameter of 3 mm were applied to the back (C7 dermatome) of the 
+right hand (pain detection threshold) or left hand (pain tolerance 
+threshold) in a target area of 2 x 3 cm. After each stimulation, the 
+handpiece was moved to avoid repeated stimulations at identical 
+spots. The pain detection threshold was defined as the stimulus 
+strength which was perceived as a distinct pin-prick; the pain toler- 
+ance threshold was defined as the stimulus strength which was per- 
+ceived as a painful pin-prick followed by an unpleasant burning pain. 
+The thresholds were calculated as the mean of five thresholds deter- 
+mined by ascending series of stimulation. 
+Plasma drug concentrations 
+Blood for drug concentration measurements was collected immedi- 
+ately after each pain threshold determination on all study days and 
+stored at - 20 °C until analysis. The plasma concentration of codeine 
+was determined by high performance liquid chromatography [22] 
+with a lower limit of detection of 10 nmol. 1-1. Morphine was assayed 
+by radioimmunoassay (Coat-A-Count, Serum Morphine kit, Diag- 
+nostic Product Corporation, Los Angeles, USA) (lower limit of de- 
+tection 4 nmol. 1-1; cross-reactivity with codeine, morphine-6-gluco- 
+ronide, and morphine-3-glucuronide less than 0.2 %). 
+Data analysis and statistics 
+Pain thresholds vary both diurnally and from day to day [23]. The 
+thresholds determined on each study day for each individual were 
+therefore transformed (hereafter designated transformed thresh- 
+olds) by multiplication by a factor which standardized the thresholds 
+before codeine or codeine-placebo to a value of 1. The mean of the 
+three transformed post-dose thresholds for each treatment served as 
+a summary measure of effect [24]. A placebo-adjusted treatment re- 
+sponse was calculated for each post dose measurement as the dif- 
+ference between the transformed thresholds on placebo/placebo 
+and on the other treatments. 
+Statistical analyses were made with Wilcoxon's test for paired ob- 
+servations, the Mann-Whitney test, and Spearman's rank correla- 
+tion. Furthermore, median and 95 % confidence intervals for dif- 
+ferences between treatments were calculated [25]. 
+Results 
+Morphine was detected in plasma samples from all the 
+volunteers after placebo/codeine, but not after quin- 
+idine/codeine (Fig.2). Codeine concentrations were 
+
+0.5- Pin-pick pain threshold 
+I/) 
+"o 
+O 
+0- 
+E~ 
+~O ~-~ -0.5 
+.n oerance hresho   
+v g _ 
+i I~ P QC PC Qp QC PC QP QC PC 
+ra -0.5 J/ ........... 
+1 2 3 
+"lime after dose (h) 
+Fig.3. Top: Medians (--) and 95 % confidence intervals (9) for the 
+differences between placebo/placebo and each of the treatments 
+QP: quinidine/placebo; QC: quinidine/codeine, and PC: placebo/co- 
+deine for the pin-prick pain thresholds. The pre-dose thresholds 
+were standardized to a value of 1. Bottom: Similar medians and 95 % 
+confidence intervals for the pain tolerance thresholds 
+Morphine Codeine 
+> 0.4- 
+_ rs = 0.83 ee rs = 0.81 • • 
+9 p < 0.001 • p < 0.001 • 
+D_ 0.2- • • oQ 
+o "~ c- r .,r, go • • 
+0- ,; 
+• • 
+__if_ o ¢ r- 
+-0.5- • • 
+"0 I I IIIIIII I I linllll I I IIIHli I I IIIItll 
+0.6- 
+rs = 0.55 rs = 0.65 
+'~ - p < 0.05 • • • p < 0.01 • 
+c~ 
+"5 0.4- 
+gg 
+$ 0.2- 
+c - • • . 
+R3 
+• ~ -0.2 • • 
+o ..O t IIIlilll I Illlllll I I IIIIIII I IIIIllll 
+o 10 100 10 100 1000 
+~- Plasma concentration (nmol • 1-1 ) 
+Fig.4. The effect of 100 mg of codeine 1 h after ingestion in relation 
+to the corresponding plasma concentrations of morphine (l@panel) 
+and codeine (right panel) in each of 16 extensive metabolizers of 
+sparteine. The effect is given as the difference between the trans- 
+formed thresholds for placebo/codeine and placebo/placebo (place- 
+bo adjusted treatment response) 
+589 
+higher after quinidine than after placebo pre-treatment 
+(median 374 vs 264 nmol. 1-1, p = 0.003). Neither mor- 
+phine nor codeine was detected in plasma samples from 
+the volunteers after placebo/placebo or after quin- 
+idine/placebo. 
+The pin-prick pain thresholds measured immediately 
+before codeine or the corresponding placebo on days 
+when quinidine pre-treatment was given (quin- 
+idine/placebo and quinidine/codeine) were not signifi- 
+cantly different from the thresholds when placebo 
+pre-treatment was given (placebo/placebo and place- 
+bo/codeine) (median 1.34 and 1.23 W vs. 1.15 and 1.20 W, 
+P = 0.25-0.74); nor were the corresponding pre-treat- 
+ment pain tolerance thresholds significantly different 
+(median 1.76 and 1.67 W vs. 1.65 and 1.46 W, P = 0.74- 
+1.0). 
+Median and 95 % confidence intervals for the differen- 
+ces between placebo/placebo and the other treatments for 
+the transformed pin-prick pain and pain tolerance thresh- 
+olds are shown in Fig. 3. Significance testing of the sum- 
+mary measure of effect is detailed in Table 1. Pin-prick 
+pain thresholds were only significantly increased by place- 
+bo/codeine, whereas pain tolerance thresholds were 
+significantly increased by both placebo/codeine and 
+quinidine/codeine compared with placebo/placebo. Qui- 
+nidine/codeine did not increase any of the thresholds com- 
+pared with quinidine/placebo. The most marked differen- 
+ces between the codeine-containing combinations and the 
+placebo-placebo combination were in the tolerance 
+thresholds. Both pin-prick and tolerance thresholds were 
+slightly higher during quinidine/placebo than during 
+placebo/placebo, but the differences did not reach statisti- 
+cal significance. 
+At i h after codeine, the interindividual variation in 
+drug concentrations was most pronounced (Fig. 2), and 
+for the placebo/codeine combination there was a signifi- 
+cant correlation between the morphine and codeine con- 
+centrations (rs = 0.67, P < 0.01). At this time-point, there 
+was highly significant correlation between the placebo- 
+adjusted treatment response for pin-prick and tolerance 
+thresholds and the plasma concentrations of both mor- 
+phine (rs = 0.83, P < 0.001 and r~ = 0.55, P < 0.05) and co- 
+Table 1. Significance testing a of the effect b on pain thresholds of the 
+different treatment combinations c 
+Comparison P-value 
+Pin-prick pain Pain tolerance 
+threshold threshold 
+PC vs. PP 0.06 0.01 
+QC vs. PP NS 0.07 
+QC vs. QP NS NS 
+QC vs. PC NS NS 
+QP vs. PP NS NS 
+a Wilcoxon's test 
+b Mean of the three post-dose thresholds transformed to standardize 
+pre-dose thresholds to a value of 1 (summary measure) 
+c Treatment combinations: PC = codeine with placebo pre-treat- 
+ment, QC = codeine with quinidine pre-treatment, PP = placebo 
+with placebo pre-treatment, QP = placebo with quinidinepre-treat- 
+ment 
+
+590 
+Table 2. The number of subjects (out of 16) reporting adverse ef- 
+fects during the treatment combinations a before (A) and after (B) 
+codeine or the corresponding placebo 
+Side effect Treatment combination 
+PP QP QC PC 
+A B A B A B A B 
+Nausea 0 0 0 0 0 2 0 1 
+Dry mouth 0 1 1 1 0 2 1 3 
+Fatigue 2 5 0 4 4 9 3 1 i 
+Dizziness 0 0 0 2 0 2 0 4 
+Headache 0 0 0 1 0 0 0 1 
+a Treatment combinations: PP = placebo with placebo pre-treat- 
+ment, QP = placebo with quinidine pre-treatment, QC = codeine 
+with quinidine pre-treatment, PC = codeine with placebo pre-treat- 
+ment 
+deine (rs = 0.81, P < 0.001 and rs = 0.65, P < 0.01) (Fig.4). 
+For the 2 and 3 h measurements of both pin-prick pain and 
+pain tolerance thresholds, there was no significant rela- 
+tion to either morphine or codeine concentrations. 
+The placebo-adjusted treatment responses of the 
+quinidine/codeine combination were not related to the co- 
+deine concentrations for either pin-prick pain or pain 
+tolerance at any of the post-dose measurements. 
+The adverse effects reported on the different treatment 
+combinations are summarized in Table 2. There was no 
+significant difference in the number of adverse effects re- 
+ported by each subject during any period (P = 0.32). 
+Discussion 
+We have found that in 16 extensive metabolizers of spar- 
+teine a single oral dose of 100 mg codeine after placebo 
+pre-treatment resulted in plasma morphine concentra- 
+tions from 6 to 62 nmol. 1-1 and caused a statistically sig- 
+nificant increase in pin-prick pain and pain tolerance 
+thresholds compared with placebo/placebo treatment. We 
+also found that morphine was undetectable in the plasma 
+after a single oral dose of 100 mg codeine preceded by 
+200 mg quinidine, confirming the importance of CYP2D6 
+in the O-demethylation of codeine [11-15, 19]. However, 
+we could not unequivocally confirm the role of morphine 
+formation for codeine hypoalgesia [15], since codeine 
+preceded by quinidine also increased pain tolerance 
+thresholds compared with placebo/placebo treatment, but 
+not compared with quinidine/placebo. 
+There are several possible explanations why codeine 
+may have a hypoalgesic effect in extensive metabolizers 
+treated with quinidine (present study) but not in poor me- 
+tabolizers (previous study [15]). Although circulating 
+morphine after codeine mainly stems from hepatic O-de- 
+methylation, it is possible that codeine hypoalgesia is due 
+to morphine formed locally in the brain [8]. CYP2D6 has 
+been identified in canine brain tissue [26, 27]. Different 
+defects in the CYP2D6 gene [28] explain why the 
+CYP2D6 isozyme is not expressed in the liver [10] or other 
+tissues in the poor metabolizers, and little or no morphine 
+is therefore likely to be formed in the brains of poor me- 
+tabolizers. Quinidine penetrates the blood-brain barrier 
+poorly [29] and thus may not inhibit CYP2D6 in the brain. 
+This postulated activity of CYP2D6 in brain thus could ex- 
+plain why codeine has a hypoalgesic effect in extensive 
+metabolizers after quinidine pre-treatment despite com- 
+plete inhibition of hepatic morphine formation. 
+Another possibilits, supported by the results of animal 
+experiments [30], is that quinidine has an unspecific local 
+analgesic effect and inhibits the release of E-type prosta- 
+glandins. Quinidine may therefore have a hypoalgesic ef- 
+fect of its own which is too weak to be detected when it is 
+given alone, but which is detectable when combined with 
+the weak effect of "pure" codeine. 
+In conclusion, we have confirmed the role of CYP2D6 
+for the hepatic O-demethylation of codeine to morphine. 
+Our results support the view that metabolically formed 
+morphine is important for codeine analgesia. However, 
+the results of the interaction studies suggest that either the 
+formation of morphine within the CNS or a hypoalgesic 
+effect of quinidine may be a complicating factors. 
+Acknowledgements. This study was financially supported by DAK- 
+Laboratoriet a/s, Copenhagen. 
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+(1972) Studies on the cutaneous pricking pain threshold in man. 
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+vals for some non-parametric analyses. Br Med J 296:1454-1456 
+26. Niznik HB, Tyndale RF, Sallee FR, Gonzales FJ, Hardwick JR 
+Inaba T, Kalow W (1990) The dopamine transporter and cyto- 
+chrome P450IID1 (debrisoquine-4-hydroxylase) in brain: Reso- 
+lution andidentification of two distinct [3N] GBR-12935 Binding 
+Proteins. Arch Biochem Biophys 276:424432 
+27. Tyndale RF, Sunahara R, Inaba T, Kalow W, Gonzales F J, Niznik 
+HB (1991) Neuronal cytochrome P450IID1 (debrisoquine/spar- 
+teine-type): Potent inhibition of activation by ( - )-cocaine and 
+nucleotide sequence identity to human hepatic P450 gene 
+CYP2D6. Mol Pharmaco140:63-68 
+28. Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA (1990) 
+Multiple mutations of the human cytochrome P450IID6 gene 
+(CYP2D6) in poor metabolizers of debrisoquine. J Biol Chem 
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+Dr. S. H. Sindrup 
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+Institute of Medical Biology 
+Odense University 
+WinslCwparken 19 
+DK-5000 Odense C 
+Denmark 

papers/17541571.md

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+# Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers.
+
+Hanne H Villesen, Kim Kristensen, Steen H Hansen, Niels-Henrik Jensen, Ulrik Skram, Lona L Christrup
+
+*European journal of clinical pharmacology* (2007)
+
+PMID: 17541571
+DOI: 10.1007/s00228-007-0306-4
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+**AIM:** After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profile with two peak plasma concentrations. A proposed explanation is that M6G is hydrolysed to morphine in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-glucuronide (M3G) and M6G. The aims of this study were to confirm and elucidate the biphasic absorption profile as well as clarify the conversion of M6G to morphine after a single oral administration of M6G in healthy volunteers.
+
+**METHODS:** The study was conducted accordingly to a nonblinded, randomised, balanced three-way crossover design in eight healthy male subjects. The subjects received 200 mg oral M6G, 50 mg oral M6G and 30 mg oral morphine. Blood samples were collected until 72 h after M6G administration and until 9 h after morphine administration. Paracetamol and sulfasalazine were coadministered with M6G as markers for the gut contents reaching the duodenum and colon, respectively.
+
+**RESULTS:** The plasma concentration peaks of M6G were seen at 4.0 (2.0-6.0) and 18 (12.0-24.0) h after 200 mg M6G and at 3.5 (2.0-6.0) and 21.3 (10.0-23.3) h after 50 mg M6G, which was in agreement with previously published results. The K(M6G_abs)/K(M6G_M6G) ratio was found to be 10.
+
+**CONCLUSION:** The pharmacokinetic profile of M6G after oral administration was confirmed and with the presence of M3G and morphine in plasma after oral administration of M6G, proof seems to be found of the constant and prolonged absorption of M6G. The K(M6G_abs)/K(M6G_M6G) ratio of 10 indicates that the second absorption peak of M6G consists of approximately 10 times more absorbed M6G than reglucuronidated M6G. However, further studies are required to determine the precise kinetics of the second absorption peak.

papers/17541571.pdf

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+PHARMACOKINETICS AND DISPOSITION
+Pharmacokinetics of morphine-6-glucuronide following oral
+administration in healthy volunteers
+Hanne H. Villesen & Kim Kristensen & Steen H. Hansen &
+Niels-Henrik Jensen & Ulrik Skram & Lona L. Christrup
+Received: 6 October 2006 / Accepted: 22 March 2007 / Published online: 31 May 2007
+# Springer-V erlag 2007
+Abstract
+Aim After oral administration, morphine-6-glucuronide
+(M6G) displays an atypical absorption profile with two peak
+plasma concentrations. A proposed explanation is that M6G
+is hydrolysed to morphine in the colon, which is then
+absorbed and subsequently undergoes metabolism in the
+liver to morphine-3-glucuronide (M3G) and M6G. The aims
+of this study were to confirm and elucidate the biphasic
+absorption profile as well as clarify the conversion of M6G
+to morphine after a single oral administration of M6G in
+healthy volunteers.
+Methods The study was conducted accordingly to a non-
+blinded, randomised, balanced three-way crossover design
+in eight healthy male subjects. The subjects received 200 mg
+oral M6G, 50 mg oral M6G and 30 mg oral morphine. Blood
+samples were collected until 72 h after M6G administra-
+tion and until 9 h after morphine administration. Paraceta-
+mol and sulfasalazine were coadministered with M6G as
+markers for the gut contents reaching the duodenum and
+colon, respectively.
+Results The plasma concentration peaks of M6G were seen
+at 4.0 (2.0 –6.0) and 18 (12.0 –24.0) h after 200 mg M6G
+and at 3.5 (2.0 –6.0) and 21.3 (10.0 –23.3) h after 50 mg
+M6G, which was in agreement with previously published
+results. The K
+M6G_abs/KM6G_M6G ratio was found to be 10.
+Conclusion The pharmacokinetic profile of M6G after oral
+administration was confirmed and with the presence of
+M3G and morphine in plasma after oral administration of
+M6G, proof seems to be found of the constant and
+prolonged absorption of M6G. The K
+M6G_abs/KM6G_M6G
+ratio of 10 indicates that the second absorption peak of
+M6G consists of approximately 10 times more absorbed
+M6G than reglucuronidated M6G. However, further studies
+are required to determine the precise kinetics of the second
+absorption peak.
+Keywords Morphine-6-glucuronide (M6G) . Morphine .
+Pharmacokinetic . Absorption . M6G formation
+Introduction
+Morphine is considered the gold standard for the treatment
+of moderate to severe pain despite its many side effects.
+The active metabolite, morphine-6-glucuronide (M6G), has
+an analgesic effect equivalent to morphine, but the side
+effects seem less frequent, particularly nausea, vomiting [ 1–
+4] and respiratory depression [ 2, 5, 6]. After oral adminis-
+tration, M6G displays an atypical absorption profile. Two
+Eur J Clin Pharmacol (2007) 63:761 –767
+DOI 10.1007/s00228-007-0306-4
+H. H. Villesen : L. L. Christrup ( *)
+Department of Pharmacology and Pharmacotherapy,
+Faculty of Pharmaceutical Sciences, University of Copenhagen,
+Universitetsparken 2,
+2100 Copenhagen, Denmark
+e-mail: llc@dfuni.dk
+K. Kristensen
+Clinical Pharmacology, Medical Science Sweden,
+AstraZeneca R&D Lund,
+Lund, Sweden
+S. H. Hansen
+Department of Pharmaceutics and Analytical Chemistry,
+Faculty of Pharmaceutical Sciences, University of Copenhagen,
+Copenhagen, Denmark
+N.-H. Jensen
+Multidisciplinary Pain Centre, Herlev University Hospital,
+Herlev, Denmark
+U. Skram
+Department of Neuroanaesthesia,
+Copenhagen University Hospital,
+Copenhagen, Denmark
+peak plasma concentrations are observed at different times.
+The first peak is seen approximately 3 –5 h after adminis-
+tration of an oral solution, whereas the second appears after
+13–20 h [ 7, 8]. The late peak is associated with the appear-
+ance of both morphine and morphine-3-glucuronide (M3G)
+in plasma. A possible explanation is that M6G is hydro-
+lysed to morphine in the colon, which is then absorbed and
+subsequently metabolised in the liver to M3G and M6G [ 7,
+9]. In a study by Chapman, a second peak was seen after
+approximately 10 h; however, neither morphine nor M3G
+was detected in plasma [ 10]. After parenteral administration
+in humans, it is generally considered that M6G is not
+metabolised [ 11–13]. The benefits of M6G in the clinical
+setting are limited due to a poor bioavailability (9 –13%) [7,
+8, 10]. However, the side effects seem less frequent,
+particularly nausea and vomiting [ 1–6]. The absorption
+enhancer TWEEN 20 seemed promising with respect to
+increasing the absorption fraction in in vitro studies [ 14].
+However, coadministration of 500 mg TWEEN 20 did not
+improve the bioavailability of orally administered M6G [ 8].
+The aims of this study was to confirm the biphasic
+absorption profile and elucidate the hydrolysis of M6G to
+morphine after a single oral dose of M6G in healthy
+volunteers.
+Materials and methods
+Study design
+The study was conducted according to a nonblinded, random-
+ised, balanced three-way crossover design with a 7-day
+washout period between each M6G administration. The
+Regional Committee on Biomedical Research Ethics for
+Frederiksberg and Copenhagen and the Danish Medicines
+Agency approved the protocol, informed consent form and
+amendments for the study. V erbal and written information
+about the study was given to the volunteers, and written
+informed consent was obtained according to the ethical
+principles stated in the Declaration of Helsinki II.
+Subjects
+Study subjects were eight healthy male volunteers aged 18 –
+35 years, all nonsmokers of normal body weight (body
+mass index between 20 and 25). Exclusion criteria included
+mental illness; alcohol or drug abuse or addiction; a history
+of alcohol abuse; illicit drug use or suspected abuse; a
+positive urine drug screen for methamphetamine, opiates,
+cocaine metabolites, cannabinoids, phencyclidine, benzo-
+diazepines, barbiturates, methadone, tricyclic antidepres-
+sants, and amphetamines; as well as long-term treatment
+with analgesics or daily use of benzodiazepines. Further,
+candidates who had received antibiotics within 4 weeks
+prior to the study; donated blood within 3 months prior to
+the study; or with deviant echocardiogram (ECG), liver or
+kidney function [lactic dehydrogenase (LDH), alanine
+aminotransferase (ALA T), aspartate aminotransferase
+(ASA T), P-creatinine], coagulation factors II, VII and X,
+or blood values (haemoglobin, potassium, sodium, alkaline
+phosphatase) were excluded from entry into the study.
+Known hypersensitivity to morphine, paracetamol, sulfasa-
+lazine, sulphonamide, or salicylate was also an exclusion
+criterion.
+Drugs
+M6G 20 mg/ml sterile solution for injection in ampoules of
+2 ml was imported from CeNeS Limited, Cambridge, UK
+and supplied by the hospital pharmacy at Herlev University
+Hospital, Denmark. Certificate of analysis showed that the
+batch contained 0.06% morphine and no detectable M3G,
+i.e. <0.03%. These amounts are not suspected to interfere
+with subsequent study results. Paracetamol tablets 500 mg,
+sulfasalazine tablets 500 mg, and morphine tablets 30 mg
+were also supplied by the hospital pharmacy. Paracetamol
+was coadministered as a marker for gastric emptying time,
+whereas sulfapyridine (the hydrolysate of sulfasalazine)
+was used as a marker for arrival of the gut content to the
+colon [ 15]. Each study subject received on different days:
+– Preparation 1: M6G 200 mg as an oral solution
+– Preparation 2: M6G 50 mg as an oral solution
+– Preparation 3: Morphine 30 mg as a tablet.
+As the aim of the study was to confirm the biphasic
+absorption profile, it was decided to repeat the doses used
+previously [
+8].
+Procedures
+Opioids, including codeine and food containing poppy
+seeds, were prohibited for 72 h and paracetamol for 24 h
+prior to each protocol day.
+Food and fluid restrictions
+Fasting from midnight was required prior to all 3 protocol
+days. During the first 6 h, the study subjects received
+500 ml of dextrose 5% as an infusion to prevent
+hypoglycaemia. Three hours after drug administration, the
+study subjects were allowed to drink 50 ml of water every
+second hour until lunch was serve d6ha f t e rd r u g
+administration. The study subjects were instructed to
+reproduce the fluid intake precisely on the 2 protocol days
+when they received the oral formulations of M6G.
+762 Eur J Clin Pharmacol (2007) 63:761 –767
+Drug administration and blood sampling
+M6G was administered as an oral solution, prepared from a
+sterile solution for injection diluted with 100 ml of
+Schweppes Bitter Lemon. Paracetamol 1,000 mg and
+sulfasalazine 500 mg were coadministered as tablets with
+the oral test solutions. Morphine was administered as a
+tablet. A peripheral vein contralateral to the glucose
+administration was used for blood sampling. For M6G
+pharmacokinetics, blood samples were obtained prior to
+drug administration, and at 15, 30 and 60 min and 2, 3, 4, 5,
+6, 8, 10, 11, 12, 16, 20, 24, 36, 48, 60 and 72 h after
+administration. For morphin e pharmacokinetics, blood
+samples were collected before and 5, 15, 30, 45, 60 and
+90 min and 2, 4, 6, 8 and 10 h after drug administration.
+The actual sampling times were noted in the individual case
+report form and subsequently used in the pharmacokinetic
+analysis. Routine vital signs — ECG including pulse rate,
+respiratory rate, blood pressure, and oxygen saturation —
+were obtained just before drug administration and every
+15 min until 12 h after drug administration. These
+parameters were recorded in the individual case report
+form. Blood samples were drawn into heparinised glass
+tubes, which were placed on ice until centrifugation at
+3,000 rpm for 10 min. Plasma was separated into tubes,
+which were stored below −20°C until analysis.
+Analytic analyses
+Quantification of plasma M6G, morphine, M3G, para-
+cetamol and sulfapyridine was done by high-performance
+liquid chromatography (HPLC) using mass spectrometry
+(MS) as the detection principle. After addition of the
+internal standard, hydromorphone, plasma samples and
+calibration standards in plasma were subject to solid-phase
+extraction using 1.0 ml of plasma on Oasis HLB SPE
+cartridges (30 mg). The final eluate was evaporated to
+dryness under nitrogen at ambient temperature, and the
+residue was dissolved in 500 μl of eluent A; 25 μl was
+injected onto the HPLC column. The LC-MS system
+consisted of an HP 1100 series chromatograph (Hewlett-
+Packard, Palo Alto, CA, USA) equipped with a Quatpump,
+a degasser, column oven (colcomp), an autosampler (ALS),
+a DAD UV detector operated at 280 nm (bandwidth 16),
+and a mass selective detector (MSD). Data were collected
+using the HP ChemStaion software, version 6.03 (Hewlett-
+Packard). The analytical column was a reversed-phase
+Zorbax Eclipse XDB (Rockland Technologies, Newport,
+DE, USA) C8 column (4.6 mm I.D. × 150 mm, 3.5 μm
+particles). A linear gradient system was applied. Eluent A
+consisted of 1% formic acid in MeCN:water (3:97 v/v) and
+eluent B 1% formic acid in MeCN:water (27:73 v/v). The
+linear gradient was applied from 100% A to 100% B over
+4 min; 100% B was maintained for 3 min and then returned
+to 100% A over 0.5 min. The flow rate was 0.5 ml/min.
+The MSD detector was equipped with an electrospray
+interface and us ed in positive mode for selected ion
+monitoring (SIM) detection of the four masses: 286.1
+(morphine and the internal standard hydromorphone, which
+are well separated in the HPLC system), 462.2 (M6G and
+M3G, which are well separated in the HPLC system), 152.1
+(paracetamol) and 250.1 (sulfapyridine). The fragmentor
+voltage was set to 100 V for the mass 286.1 and 120 V for
+the masses 152.1, 250.1 and 462.2. The voltage over the
+capillary was kept at 3,000 V . The temperature of the
+nitrogen drying gas was set to 350°C, with a flow rate of
+13 l/min. The nebulizer gas pressure was 30 psi. Limit of
+quantification (LOQ) for morphine and M3G/M6G was
+0.5 nmol/l and 1.0 nmol/l, respectively. Linearity of the
+calibration curve was proven from 0.5 to 50.000 nmol/l.
+This was used to detect M6G. Narrow ranges were used to
+detect morphine and M3G 0.5 –50 nmol/l and 0.5 –
+1,000 nmol/l, respectively.
+Data analysis
+Pharmacokinetic analysis
+Individual plasma concentrations for M6G were analysed
+using WinNonLin, V ersion 3.3 (Pharsight Corporation,
+Mountain View, CA, USA). The following pharmacokinetic
+parameter estimates were determined using noncompart-
+mental analysis. From the data obtained after oral admin-
+istration, area under the curve (AUC)
+0–24,A U C0–72 and lag
+time [the time prior to the time corresponding to the first
+measurable (nonzero) concentration (t lag)] were determined.
+Maximum plasma concentration (C max) and time to reach
+maximum plasma concentration (t max) were registered as
+the actual obtained values by visual inspection of the
+individual curves. As M6G is absorbed biphasically, the
+first t
+max was to correspond to the first C max. The second
+tmax was to correspond to the C max observed after
+sulfapyridine was detected in plasma, e.g. when M6G was
+expected to have reached the colon.
+The second absorption peak seen after oral administra-
+tion of M6G is believed to consist of M6G directly
+absorbed after oral administration and M6G produced by
+glucuronidation of morphine. In order to determine the ratio
+of reglucuronidated M6G to absorbed M6G, the following
+hypotheses are made:
+1. The formation of M3G after M6G administration
+(M3G_M6G) has to equal the one after morphine
+administration (M3G_MOR), as M6G is not able to
+interconvert to M3G, which can then only can be
+produced by glucuronidation of morphine.
+Eur J Clin Pharmacol (2007) 63:761 –767 763
+2. Likewise, the M6G formed by glucuronidation of
+morphine (M6G_M6G) must equal the M6G formed
+after morphine administration (M6G_MOR).
+3. The formation of M6G, which makes up the second
+absorption peak (M6G_app), consists of directly
+absorbed M6G (M6G_abs) as well as formation of
+M6G by glucuronidation of morphine (M6G_M6G).
+According to hypothesis 1 and 2, the subsequent
+equation follows:
+K
+M 3G MOR=KM 6G MOR ¼ KM 3G M 6G=KM 6G M 6G ð1Þ
+The different rate constants of M3G and M6G after
+morphine administration (K M3G_MOR /KM6G_MOR )a n d
+M3G after M6G administration (K M3G_M6G) are determined
+by using the method of residuals [ 16]. K M6G_M6G can be
+determined by rearranging Eq. 1.
+The M6G rate constant (K M6G_app) hypothesised in
+hypothesis 3 can also be determined by using the method
+of residuals on the second absorption peak. K M6G_M6G are
+given by Eq. 1 and K M6G_abs can be determined by
+rearranging Eq. 2:
+KM 6G M 6G þ KM 6G abs ¼ KM 6G app ð2Þ
+Statistical analysis
+GraphPad Prism version 4.00 for Windows (GraphPad
+Software, San Diego, CA, USA) was used for all statistical
+analyses. A paired t test with two-tail P value was used to
+test differences in normally distributed data (dose-normalised
+C
+max and AUC) between the two oral treatment means.
+Normality was tested by test for Gaussian distribution.
+Wilcoxon matched pairs signed rank sum test with two-tail
+P value was used to test differences in nonnormally
+distributed data (t
+max). A P value of 0.05 was considered
+statistically significant.
+Results
+All results are presented as mean values with standard
+deviation (SD) or 95% confidence interval (95% CI) or as
+median with range. Mean age, height and weight of the
+study subjects was 25±5 years, 182±2.7 cm, and 75.4±
+5.5 kg (BMI 23±1.8), respectively. All study subjects
+completed all three arms of the study. Side effects were
+mild to moderate and did not require medical attention.
+Pharmacokinetic analysis
+Oral administration of M6G
+Figure 1 shows individual plasma concentrations versus time
+profiles of M6G after oral administration. There was
+considerable intervariability between subjects when M6G
+was administered orally (see Table 1).
+Two plasma concentration peaks were seen at 4.0 (2.0 –
+6.0) and 18 (12.0 –24.0) h after 200 mg M6G and at 3.5
+(2.0–6.0) and 21.3 (10.0 –23.3) h after 50 mg M6G;
+however, neither of the time differences was statistically
+significant ( P=0.3 and 0.8, respectively). The C
+max
+corresponding to the first and second t max after 200 mg
+M6G was 323±194 and 214±75 nmol/l, respectively, and
+76±58 and 53±16 nmol/l, respectively, after 50 mg M6G.
+The AUC
+0–72 after 200 mg M6G and after 50 mg M6G was
+7,639±1,762 nmol/l h and 1,903±473 nmol/l h, respectively.
+When the AUCs were dose-normalised, no statistically
+significant difference was seen ( P=0.85 ).
+Paracetamol, which was coadministered as a marker for
+arrival time in the small intestine, was detectable in plasma
+Fig. 1 Individual morphine-6-glucuronide (M6G) concentration after
+oral administration of M6G 200 mg ( a) and 50 mg ( b)
+764 Eur J Clin Pharmacol (2007) 63:761 –767
+at the first sampling time (15 min) in all study subjects after
+administration of both 50 mg and 200 mg M6G. T max was
+2.0±1.1 and 1.4±0.8 h after coadministration with 50 mg
+and 200 mg M6G, respectively, which is in accordance with
+the first t
+max seen after M6G administration. Arrival time in
+the colon was to be determined by the time of the first
+appearance of sulfapyridine in plasma. The t
+lag for
+sulfapyridine, which indicates the time for the gut content
+to reach the colon, varied considerably, from 15 min to 5 h.
+M3G and morphine was found to appear in plasma
+concurrently with sulfapyridine. Consequently, high vari-
+ance in t
+lag for morphine was seen (16 min –12 h). T max for
+sulfapyridine was 20±4 and 22±3 h after coadministration
+with 50 mg and 200 mg M6G, respectively, which is in
+accordance with the second t max seen after M6G adminis-
+tration. The mean plasma concentration profiles of M6G,
+M3G, morphine, paracetamol and sulfapyridine are shown
+in Fig. 2.
+Oral administration of morphine
+Tlag for orally administered morphine was 6±11 min. Five
+of the eight subjects had detectable concentrations of
+morphine in the first sample after administration. Time to
+C
+max was 56±40 min, and the AUC was 119 (73 –181)
+nmol/l h. Four of eight study subjects (nos. 4, 5, 6 and 7)
+had a washout period of only 5 days between treatment
+with M6G 200 mg and treatment with morphine 30 mg. Of
+these four, three had relatively large concentrations of
+M6G, M3G and morphine (only two) in the sample taken
+before morphine administration and the first sample taken
+after (corresponding to 96 h on Fig. 3). The contribution of
+the residual area, however, accounts for only 2 –5% of the
+AUC of M6G formed after morphine administration
+calculated by extrapolating the curve for M6G. Similarly
+for morphine, the contribution of morphine from M6G
+200 mg only accounts for 3% of the total AUC. The
+contribution from M6G 200 mg is considered negligible
+and is not accounted for in the subsequent calculations.
+The AUCs
+0–9 of M6G and M3G formed after morphine
+were 815 (730 –1,147) and 6,009 (4,552 –7,232) nmol/l h,
+respectively, giving an M3G/M6G ratio of 7.4. The rate
+constant of M3G and M6G after morphine administration
+(K
+M3G_MOR and K M6G_MOR) was determined to be 0.038±
+0.0168 min −1 a n d0 . 0 3 5 5 ± 0 . 0 1 5 5m i n−1, respectively.
+KM3G_M6G and K M6G_app were 0.0014±0.0006 min −1 and
+0.0160±0.0176 min −1, respectively. The K M6G_abs was
+determined to be 0.0145, giving a K M6G_abs/KM6G_M6G
+ratio of approximately 10.
+Table 1 Pharmacokinetic parameters of morphine-6-glucuronide (M6G)
+Oral Oral Significance
+Dose (mg) 50 200
+Tmax1 (h) 3.5 (2.0 –6.0) 4.0 (2.0 –6.0) No ( P=0.3)
+Tmax2 (h) 21.3 (10.0 –23.3) 18 (12.0 –24.0) No ( P=0.8)
+Cmax1 (nmol/l) 76±58 323±194
+Cmax2 (nmol/l) 53±16 214±75
+AUC0–24 (nmol/l/h) 983±398 4317±1602
+AUC0–24/dose (nmol/l/h/mg) 20±8 22±8
+AUC0–72 (nmol/l/h) 1903±473 7639±1762
+AUC0–72/dose (nmol/l/h/mg) 38±10 38±9 No ( P=0.85)
+Tmax time to reach maximum plasma concentration, Cmax maximum plasma concentration, AUC area under the curve
+Parametric data are presented as mean ± standard deviation (SD), whereas nonparametric data are presented as median (range)
+Fig. 2 Mean plasma concentration profiles of morphine-6-glucuronide
+(M6G) ( square), morphine-3-glucuronide (M3G) ( diamond), mor-
+phine ( triangle ), paracetamol ( circle) and sulfapyridine ( invert
+triangle) after oral administration of 200 mg M6G
+Eur J Clin Pharmacol (2007) 63:761 –767 765
+Discussion
+The pharmacokinetic parameters estimated after oral ad-
+ministration were also within the range of previously
+published data [ 7, 8]. Two separate plasma concentration
+peaks were seen after oral administration. The second
+plasma concentration peak has been explained by hydroly-
+sis of M6G to morphine, which then undergoes glucu-
+ronidation to M6G and M3G, hence the second peak. The
+occurrence of both M3G and morphine concurrently with
+the presence of sulfapyridine in plasma supports the theory
+that M3G is not able to interconvert to M6G and hence has
+to be produced by glucuronidation of morphine in the liver.
+In the present study, the plasma concentration peaks after
+50 mg occurred slightly later than previously published by
+Villesen et al. (t
+1: 3.5 vs. 2.5; t 2: 21.3 vs. 18 h,
+respectively). However, the differences are not statistically
+significant (t
+1: P=0.4; t 2: P=0.5). For both C maxs and
+AUCs, linearity is seen between the two doses.
+The second plasma concentration peak after 200 mg
+M6G was seen 18 h after administration, with a
+corresponding C max of 214±75 nmol/l. In four study
+subjects, the washout period was only 5 days, and more
+than 96 h after drug administration, M6G, M3G and
+morphine were still detectable in plasma in three of four
+study subjects. All three had relatively high plasma
+concentrations of sulfapyridine (Fig. 3)a t9 6h .
+The K
+M6G_abs/KM6G_M6G ratio of 10 indicates that the
+second absorption peak of M6G consists of approximately
+10× more absorbed M6G than reglucuronidated M6G. This
+means that the absorption of M6G happens throughout the
+entire gastrointestinal tract. The clinical consequense is that
+orally administered M6G acts as a physiological sustained-
+release system in itself, as earlier purposed by Stain-Texier
+et al. in 1998 [ 9]. However, great variability exists, and
+further pharmacokinetic modelling will be required.
+Conclusion
+The pharmacokinetic profile of M6G after oral administra-
+tion was confirmed, and with the presence of M3G and
+morphine in plasma after administration of M6G seems to
+be proof of the constant and prolonged absorption of M6G.
+The K
+M6G_abs/KM6G_M6G ratio of 10 indicates that the
+second absorption peak of M6G consists of approximately
+10 times more absorbed M6G than reglucuronidated M6G.
+However, further studies are required to determine the
+precise kinetics of the second absorption peak.
+Fig. 3 Individual plasma con-
+centration profiles of morphine-
+6-glucuronide (M6G) ( square),
+morphine-3-glucuronide (M3G)
+(diamond), morphine ( triangle),
+paracetamol ( circle) and sulfa-
+pyridine ( invert triangle ) after
+oral administration of 200 mg
+M6G for four of the study
+subjects
+766 Eur J Clin Pharmacol (2007) 63:761 –767
+Acknowledgements This study was partly supported by CeNeS
+Limited, Cambridge, UK. All the authors are independent of CeNeS
+Limited.
+References
+1. Romberg R, Olofsen E, Sarton E, den Harting J, Taschner PEM,
+Dahan A (2004) Pharmacokinetic-pharmacodynamic modeling of
+morphine-6-glucuronide-induced analgesia in healthy volunteers.
+Anesthesiology 100:120 –133
+2. Thomson PI, Joel S, John L, Wedzicha JA, Maclean M, Slevin M
+(1995) Respiratory depression following morphine and morphine-
+6-glucuronide in normal subjects. Br J Clin Pharmacol 40:145 –
+152
+3. Skarke C, Darimont J, Schmidt H, Geisslinger G, Lötsch J (2003)
+Analgesic effects of morphine and morphine-6-glucuronide in an
+transcutaneous electric pain model in healthy volunteers. Clin
+Pharmacol Ther 73:107 –121
+4. Cann C, Curran J, Milner T, Ho B (2002) Unwanted effects of
+morphine-6-glucoronide and morphine. Anaestesia 57:1200 –1203
+5. Romberg R, Olofsen E, Sarton E, Teppema L, Dahan A (2003)
+Pharmacodynamic effect of morphine-6-glucuronide versus mor-
+phine on hypoxic and hypercapnic breathing in healthy volun-
+teers. Anesthesiology 99:788 –798
+6. Peat SJ, Hanna MH, Woodham M, Knibb A, Ponte J (1991)
+Morphine-6-glucuronide: effects on ventilation in normal volun-
+teers. Pain 45:101 –104
+7. Penson RT, Joel SP , Roberts M, Gloyne A, Beckwith S, Slevin
+ML (2002) The bioavailability and pharmacokinetics of subcuta-
+neous, nebulized and oral morphine-6-glucuronide. Br J Clin
+Pharmacol 53:347 –354
+8. Villesen HH, Hedal B, Engbaek J et al (2006) Pharmacokinetics
+of M6G following intravenous and oral administration in healthy
+volunteers. Acute Pain 8:63 –71
+9. Stain-Texier F, Sandouk P , Scherrmann J-M (1998) Intestinal
+absorption and stability of morphine-6-glucuronide in different
+physiological compartments of the rat. Drug Metab Dispos
+26:383–387
+10. Chapman DJ (1990) Analysis and pharmacokinetics of morphine
+and morphine-6-glucuronide. University of Surrey, UK
+11. Lötsch J, Stockmann A, Kobal G et al (1996) Pharmacokinetics of
+morphine and its glucuronides after intravenous infusion of
+morphine and morphine-6-glucuronide in healthy volunteers. Clin
+Pharmacol Ther 60:316 –325
+12. Osborne R, Thompson P , Joel S, Trew D, Patel SS, levin M
+(1992) The analgesic activity of morphine-6-glucuronide. Br J
+Pharmacol 34:130 –138
+13. Lötsch J, Weiss M, Kobal G, Geisslinger G (1998) Pharmacokinet-
+ics of morphine-6-glucuronide and its formation from morphine
+after intravenous administration. Clin Pharmacol Ther 63:629 –639
+14. Christrup LL, Froekjaer S, Villesen HH (2006) Morphine-6-
+Glucuronide: the clinical potential after oral administration.
+Permation of isolated rat gut segments. Eur J Pharm Biopharm.
+unpublished data
+15. Sunesen VH, V edelsdal R, Kristensen HG, Christrup L, Mullertz
+A (2005) Effect of liquid volume and food intake on the absolute
+bioavailability of danazol, a poorly soluble drug. Eur J Pharm Sci
+24:297–303
+16. Rowland M, Tozer TN (1995) Clinical pharmacokinetics. Con-
+cepts and applications, 3rd edn. Lippincott Williams & Wilkins,
+Philadelphia
+Eur J Clin Pharmacol (2007) 63:761 –767 767

papers/7002186.md

@@ -0,0 +1,16 @@
+# Kinetics and metabolism of paracetamol and phenacetin.
+
+L F Prescott
+
+*British journal of clinical pharmacology* (1980)
+
+PMID: 7002186
+DOI: 10.1111/j.1365-2125.1980.tb01812.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+1 The rate of absorption of oral paracetamol depends on the rate of gastric emptying and is usually rapid and complete. The mean systemic availability is about 75%. 2 Paracetamol is extensively metabolized and the plasma half-life is 1.5-2.5 hours. About 55% and 30% of a therapeutic dose is excreted in the urine as glucuronide and sulphate conjugates, respectively, whereas mercapturic acid and cysteine conjugates (representing conversion to a potentially toxic intermediate metabolite) each account for some 4% of the dose. Paracetamol metabolism is age- and dose-dependent. 3 With hepatotoxic doses, paracetamol metabolism is impaired and the half-life prolonged. Sulphate conjugation is saturated and the proportion excreted as mercapturic acid and cysteine conjugates is increased. 4 The renal clearance of paracetamol depends on urine flow rate by not pH. The renal clearances of the glucuronide and sulphate conjugates often exceed the glomerular filtration rate and are independent of urine flow and pH. 5 Phenacetin absorption depends on formulation. It is extensively metabolized to paracetamol and minor metabolites are probably responsible for toxicity.

papers/7002186.pdf

@@ -0,0 +1,3 @@
+version https://git-lfs.github.com/spec/v1
+oid sha256:1a8a05a1c08796877b55fa2546797e672a0cf0ac7abec6cac06d63ffbb1b500c
+size 1047396

papers/7002186.txt

@@ -0,0 +1,765 @@
+Br.J.clin.Pharmac.(1980),10,291S-298S
+KINETICSAND METABOLISM
+OFPARACETAMOL AND PHENACETIN
+L.F.PRESCOTT
+UniversityDepartmentofTherapeuticsandClinicalPharmacology,TheRoyalInfirmary,
+Edinburgh,UK
+1 Therateofabsorptionoforalparacetamoldependsontherateofgastricemptyingandisusually
+rapidandcomplete.Themean systemicavailabilityisabout757o.
+2 Paracetamolisextensivelymetabolizedandtheplasmahalf-lifeis1.5-2.5hours.About55%oand
+3007ofatherapeuticdoseisexcretedintheurineasglucuronideandsulphateconjugates,respectively,
+whereasmercapturicacidandcysteineconjugates(representingconversiontoa potentiallytoxic
+intermediatemetabolite)eachaccountforsome4%oofthedose.Paracetamolmetabolismisage-and
+dose-dependent.
+3 Withhepatotoxicdoses,paracetamolmetabolismisimpairedandthehalf-lifeprolonged.Sulphate
+conjugationissaturatedandtheproportionexcretedasmercapturicacidandcysteineconjugatesis
+increased.
+4 TherenalclearanceofparacetamoldependsonurineflowratebynotpH.Therenalclearancesof'
+theglucuronideandsulphateconjugatesoftenexceedtheglomerularfiltrationrateandare
+independentofurineflowandpH.
+5 Phenacetinabsorptiondependsonformulation.Itisextensivelymetabolizedtoparacetamoland
+minormetabolitesareprobablyresponsiblefortoxicity
+Paracetamol
+PARACETAMOL(acetaminophen,N-acetyl-p-amino-
+phenol,4-hydroxyacetanilide)isamoderatelywater-
+andlipid-solubleweakorganicacid.IthasapKa
+valueof9.5andisthereforelargelyunionizedover
+thephysiologicalrangeofpH.
+Absorption
+Paracetamolisinvariablytakenorally.Absorption
+fromthegastrointestinaltractisbypassivetransport
+(Bagnall,Kelleher,Walker& Losowsky,1979)and
+thereisonlyminormetabolismofthedrugbythe
+gastrointestinalmucosaintherat(Josting,Winne&
+Bock,1976).Inman,paracetamolabsorptionis
+negligiblefromthestomachbutveryrapidfromthe
+smallintestineandtherateofabsorptiontherefore
+dependsontherateofgastricemptying(Heading,
+Nimmo,Prescott& Tothill,1973).Absorptionis
+slowedifgastricemptyingisdelayedbyfood,
+posture,diseaseanddrugssuchaspropanthelineand
+narcoticanalgesics,butthetotalamountabsorbedis
+notdecreased(McGilveray&Mattok,1972;Nimmo,
+Heading,Tothill& Prescott,1973;Nimmo,
+Heading,Wilson,Tothill& Prescott,1975;Nimmo
+&Prescott,1978).
+Infastinghealthysubjects,absorptionofpara-
+cetamolinsolutionisveryrapidwithpeakplasma
+concentrationsoftenoccurringwithin15-30minof
+ingestion.Absorptionfromtabletsisusuallyslower,
+andinpracticalclinicalconditionstheremaybeas
+muchasan80-foldrangeinplasmaconcentrations
+1h afteradministrationofa therapeuticdose
+(Prescott,1974).
+Distribution
+Paracetamolisrapidlyandrelativelyuniformly
+distributedinthetissues(Brodie& Axelrod,1949).
+Theratioofconcentrationsinredbloodcellsand
+plasmaisabout1.2:1 andbindingtoplasma
+proteinsisinsignificant(Gazzard,Ford-Hutchinson,
+Smith& Williams,1973).Theapparentvolumeof
+distributionofparacetamolinmanisabout0.91/kg
+(seebelow).
+Metabolism
+Paracetamolisextensivelymetabolizedandonly
+2-5Woofatherapeuticdoseisexcretedunchangedin
+theurine.Althoughbiotransformationoccurs
+predominatelyintheliver,theremay besome
+metabolismofthedruginthegutandkidney
+(Josting,Winne& Bock,1976;Jones,Sundby,
+Ormstad& Orrenius,1979;Mitchell,McMurtry,
+Statham&Nelson,1977).
+Themajormetabolitesofparacetamolarethe
+sulphateandglucuronideconjugates,butaminor
+3$MacmillanPublishersLtd19800306-5251/80/140291-08$01.00 291S
+292S L.F.PRESCOTT
+20r
+C
+0
+.5
+0
+E
+L
+0 2 4 6 8
+Timeafteradministration(h)
+Figure1 Meanplasmaconcentrationsofparacetamol
+(0; t4=2.3)anditssulphate(Q)andglucuronide
+conjugates(0)(expressedasparacetamolequivalents)in
+8healthysubjectsafteranoraldoseof20mg/kg.
+fractionisconvertedbyhepaticmixedfunction
+oxidasetoa highlyreactivealkylatingmetabolite.
+Thismetaboliteisnormallyrapidlyinactivatedby
+conjugationwithreducedglutathioneandeventually
+excretedintheurineascysteineandmercapturicacid
+conjugates.Largedosesofparacetamolcauseacute
+hepaticnecrosisas a resultofdepletionof
+glutathioneandofcovalentbindingoftheexcess
+reactivemetaboliteto vitalcellconstituents
+(Mitchell,Jollow,Potter,Davis,Gillette& Brodie,
+1973;Mitchell,Thorgeirsson,Potter,Jollow&
+Keiser,1974).Paracetamolcausesacuterenaltubular
+necrosisbya similarmechanismanditstoxicityis
+dependenton microsomalenzyme activityand
+glutathioneavailability(Mitchelletal.,1977).In
+keepingwiththesemechanisms,liverdamageand
+renalfailurefollowingparacetamoloverdosagecan
+bepreventedbyearlyadministrationofsulphydryl
+compoundssuchas N-acetylcysteine(Prescott,
+Illingworth,Critchley,Stewart,Adam&Proudfoot,
+1979).Otherminormetabolitesof paracetamol
+includeconjugatesof3-methoxy-,3-hydroxy-and3-
+thiomethylparacetamol(Andrews,Bond,Burnett,
+Saunders& Watson,1976;Klutch,Levin,Chang,
+Vane&Conney,1978).
+Paracetamolmetabolismisage- anddose-
+dependent.Inhealthyyoung adultstheplasma
+paracetamolhalf-lifefollowingatherapeuticdoseis
+about2h(range1.5-2.5h),andabout40o,30%0,
+55%,407and4% ofthedoseisexcretedintheurine
+in24hasunchangedparacetamolanditssulphate,
+glucuronide,cysteineand mercapturicacid
+conjugates,respectively.Inneonatesandyoung
+children,however,glucuronideconjugationis
+deficient.Thehalf-lifeisprolongedandsulphate
+conjugationisthedominantmetabolicpathway
+(Levy,Khanna,Soda,Tsuzuki&Stern,1975;Miller,
+Roberts& Fischer,1976).Althoughithasbeen
+claimedthatparacetamolmetabolismisimpairedin
+theelderly(Briant,Dorrington,Cleal& Williams,
+1976),themeanplasmahalf-life(2.17h)iswell
+withintherangereportedinyoungadultsbymany
+investigators.Theplasmaparacetamolhalf-lifeis
+prolongedinchronicliverdisease,buttoalesser
+extentthanantipyrineandlignocaine,andoverallits
+metabolismisquantitativelythesameasinhealthy
+subjects(Forrest,Finlayson,Adjepon-Yamoah&
+Prescott,1977;Forrest,Adriaenssens,Finlayson&
+Prescott,1979).Paracetamolmetabolismisalso
+impairedinsevereparacetamolpoisoning,and
+prolongationoftheplasmahalf-lifeisthenareliable
+indexoftheseverityofliverdamage(Prescott&
+Wright,1973).
+Paracetamolmetabolismhasbeencomparedin
+healthyadultsgivenanoraldoseof20mg/kgand
+patientswithparacetamolpoisoningreceiving
+differenttreatments(Prescottetal.,1979).Plasma
+andurineconcentrationsofparacetamolandits
+metaboliteshavebeenmeasuredby high
+performanceliquidchromatography(Adriaenssens&
+Prescott,1978).The20mg/kgdoseisrapidly
+absorbedandafter3htheplasmaconcentrationsof
+glucuronideexceedthoseoftheparentdrug(Figure
+1).Thereisasimilarrelationshipbetweentheplasma
+concentrationsofparacetamolanditsglucuronide
+conjugateinpatientswithparacetamolpoisoning
+withoutliverdamage,butinthosewhodeveloped
+severeliverdamage(plasmaaminotransferases>
+1,000IU/1)paracetamolmetabolismisimpaired,the
+half-lifeisprolongedandglucuronideconcentrations
+arelowerthanthoseoftheunchangeddrugatall
+times(Figures1-3).Theimpairmentofglucuronide
+conjugationseemstobedependentonlyontheextent
+ofliverdamageandisunrelatedtotreatment(except
+insofarthatearlytreatmentpreventsliverdamage).
+Thesulphateconjugationofparacetamolbecomes
+saturatedinadultswithinthetherapeuticdoserange
+(Levy&Yamada,1971).Afteradoseof20mg/kg,
+themean maximumplasmaconcentrationof
+paracetamolsulphateisabout5pg/ml,andthe
+concentrationsareonlyslightlyhigherinuntreated
+poisonedpatients.However,patientsreceivingearly
+treatmentwithN-acetylcysteineandcysteamineshow
+amarkedincreaseinplasmaconcentrationsofthe
+sulphate,andthereisaminordelayedincreasein
+thosewithsevereliverdamagereceivinglatetreat-
+ment(Figures1-3).Theseresultsareconsistentwith
+saturationofsulphateconjugation,depletionof
+inorganicsulphatewithlargedosesofparacetamol,
+andincreasedavailabilityofsulphatefollowingearly
+METABOLISMOFPARACETAMOL&PHENACETIN 293S
+a
+100k
+301-
+10-
+1 0 2
+0 10 20
+b
+0 10 20 30
+Timeafteringestion(h)
+Figure2 Meanplasmaconcentrationsofparacetamol(@)anditssulphate(0)andglucuronideconjugates(A)
+(expressedasparacetamolequivalents)inpoisonedpatients(n=4)withoutliverdamagereceivingnotreatment(a)
+andearlytreatmentwithN-acetylcysteine(n=14)andcysteamine(n=4).Paracetamoltt:a,3.4h;b,3.7hours.
+b
+10 20 30 0 10 20 30
+Timeafteringestion(h)
+Figure3 Meanplasmaconcentrationsofparacetamol(-)anditssulphate(0)andglucuronideconjugates(A)
+(expressedasparacetamolequivalents)inpoisonedpatients(n= 5)withsevereliverdamagereceivingnotreatment
+(a)andlate(>10h)treatmentwithN-acetylcysteine(n= 9)andcysteamine(n= 4).Paracetamolt+:a,6.7h;b,6.9
+hours.
+treatmentwithN-acetylcysteine.Intravenoussodium
+sulphatehasasimilareffecton sulphateconjugation
+ofparacetamolinrats(Galinsky,Slattery& Levy,
+1979).
+Theurinaryexcretionofparacetamolandits
+metabolitesafteroverdosageandaftera doseof
+20mg/kgisshowninTable1.Inthelattergroup
+therecoveryofsulphateandglucuronideconjugates
+isabout30%0and55%0ofthedose,respectively,and
+excretionisvirtuallycompletewithin24hours.The
+sulphateconjugateaccountsfora veryhighinitial
+butrapidlyfallingproportionofthetotalexcreted
+(Figure4),againconsistentwitha limitedand
+decreasingcapacityforsulphateconjugation.
+300
+._o
+Co
+Eenco 3
+a300r
+100iF0)
+Z.
+C
+0
+Co
+C0
+Co
+E
+Co
+30F
+10I
+3
+.0 I IIl '
+294S L.F.PRESCOTT
+60r
+0
+E(a 50C',n
+C.
+0& 40
+.0
+E 30
+-'a
+O 20ECu
+0 1
+-0co5
+-A
+(0L I i A I I L.
+0 2 4 6 8 10 12 18
+Timeafteradministration(h)
+Figure4 Changesinthemeanproportionalurinary
+excretionofparacetamol(0)anditssulphate(0),
+glucuronide(0),cysteine(A)andmercapturicacid
+conjugates(U)(expressedasparacetamolequivalents)
+withtimeafteranoraldoseof20mg/kgineighthealthy
+subjects.
+0
+0._'a
+E
+Cu._
+0
+c
+0
+-oCu
+0
+E'ac
+Q
+Cu
+4-
+00
+VD
+0.
+40
+0
+0'Uw
+0la
+Cu
+0
+04
+(U
+.0
+CuCu
+.c
+co
+0
+O. coCo
+0
+.IV
+C)
+CO
+C)
+Cu
+C)
+0_
+cn
+'0
+._
+C)
+Cu
+C).w
+Cu 0) ...
+Cu ,
+Cu'
+ 2 ._
+Cu;
+ .,C
+Q 'o
+C)Cu
+ .,Cu
+80r
+60
+40[
+20
+IJ_ A I '
+0 20 40 60
+Timeafteroverdose(h)
+Figure5 Changingpatternofrelativeurinaryexcretion
+ofthesulphate(0),glucuronide(0),andcysteineplus
+mercapturicacidconjugates(0)ofparacetamol
+(expressedasparacetamolequivalents)inapatientwith
+fatalliverdamageafterparacetamoloverdosage
+receivingsupportivetherapy.
+en (S_s'tt 00 r- O
+ B a _______
+ jct o NItt- No 00 V
+W;i ,6vo
+1.NO d* N 'O*
+-u_ f r)On -_ f)e C _-
+Q- 0 0or-o0e0 0r6__
+ce 000
+00 WI,00 n 00oe 00
+ u zu z0
+0."
+co C40
+C) 0 o
+c E0 Q ~0 >
+ Cu_X
+C)
+C)
+.Cu
+ Z
+C)
+ Cu)
+o.2
+ oCu
+'0o
+* +-
+1.q.l
+METABOLISMOFPARACETAMOL&PHENACETIN
+Inthepoisonedpatientsonly10-12%ofthetotal
+excretedisrecoveredassulphateandthereisa
+correspondingincreaseintheexcretionof
+glucuronideandunchangeddrug(Table1).Asthe
+amountofparacetamolremaininginthebody
+decreases,thereisa progressiveincreaseinthe
+proportionrecoveredassulphate(Figure5)andin
+somepatientsitbecomesthedominanturinary
+metabolite.
+Theproductionofcysteineandmercapturicacid
+conjugatesofparacetamolisofmajortoxicological
+significance(Mitchelletal.,1973;1974;1977).
+About4%ofadoseof20mg/kgisrecoveredinthe
+urineascysteine,and4% asmercapturicacid
+conjugates.Irrespectiveoftreatment,therecoveryis
+virtuallythesameinthepoisonedpatientswithout
+liverdamage,butthereisasignificantincreasein
+thosewithsevereliverdamage(Table1).Themean
+totalurinaryrecoveryofcysteineandmercapturic
+acidconjugatesisalmosttwiceashighinpatients
+withsevereliverdamagethaninthosewithout(1.95
+and1.13g,respectively).Thepeakpercentage
+excretionofthecysteineandmercapturicacid
+conjugatesisusuallydelayedforabout30h in
+patientswithsevereliverdamage,whenthesetwo
+metabolitesaccountfor20-50%ofthetotalexcreted
+(Figure5).
+Treatmentwithcysteamineandmethioninehas
+littleifanyeffectonthepatternofexcretionof
+paracetamolmetabolitesbutsulphate,cysteineand
+mercapturicacidconjugatesareclearlyincreasedby
+N-acetylcysteine(Table1).
+Renalexcretion
+Themeanrenalclearanceofparacetamolinthe
+healthysubjectsgiven20mg/kgwas13ml/minute.
+Asimilarvaluehasbeenreportedinapreviousstudy,
+andtheclearancedependsonurineflowratebutnot
+pH (Prescott& Wright,1973).Paracetamolseems
+tobefilteredattheglomeruluswithsubsequent
+extensivetubularreabsorption.
+Themeanrenalclearancesofparacetamolsulphate
+andglucuronideare166and130ml/min,respec-
+tively,andthereisnocorrelationwithurineflowor
+pH.Thesefindingsindicateactiverenaltubular
+secretion,andsimilarmechanismsoftherenal
+excretionofparacetamolandtheseconjugateshave
+beendemonstratedindogs(Duggin&Mudge,1975).
+Theplasmahalf-lifeofparacetamolisnotincreased
+inpatientswithimpairedrenalfunction,butthereis
+accumulationandretentionofconjugates(Prescott,
+1969;0ie,Lowenthal,Briggs&Levy,1975).
+Kinetics
+Thekineticsofparacetamolabsorption,distribution
+andeliminationhavebeenstudiedbymany
+50r
+201
+E
+(0
+'5
+E
+C.)0.
+EC'Co
+101
+5
+2
+0 2 4
+Timeafteradministration(h)
+6
+Figure6 Meanplasmaconcentrationsofparacetamolin
+fourhealthysubjectsfollowingintravenous(-)andoral
+doses(0)of12mg/kgonseparateoccasions.
+investigators(Nelson&Morioka,1963;Cummings,
+King& Martin,1967;Levy& Yamada,1971;
+Prescott&Wright,1973;0ieetal.,1975;Clements&
+Prescott,1976;Briantetal.,1976;Rawlins,
+Henderson& Hijab,1977;Clements,Heading,
+Nimmo&Prescott,1978;Slattery&Levy,1979;and
+others).A newpharmacokineticmodelhasrecently
+beendevelopedtotakeintoaccountthecriticaleffect
+ofvariationingastricemptyingrateonparacetamol
+absorptioninman.Withthismodelthereisexcellent
+agreementbetweenobservedandcalculatedplasma
+paracetamolconcentrationswithdifferentratesand
+patternsofgastricemptying.Themeanhalf-timefor
+paracetamolabsorptionfromthesmallintestineis
+lessthan7min(Clementsetal.,1978).
+Aftertheintravenousinjectionof12mg/kgof
+paracetamolover2mininhealthyadults,plasma
+concentrationsdecreaserapidlyduringthefirsthour
+followedbyaslowereliminationphase(Figure6).
+Thedataareconsistentwithatwo-compartment
+openmodel,andtheresultsofconventionalpharma-
+cokineticanalysisaresummarizedinTable2.The
+volumeofdistributionandtotalbodyclearancein
+a 70kgadultareabout651and380ml/min,
+respectively.Inthesamesubjectssubsequentlygiven
+thesamedoseofparacetamolorallyinsolution,
+absorptionisveryrapidwiththemeanpeakplasma
+concentrationoccurringat15min;aftera short
+distributivephase,concentrationsdeclineinparallel
+295S
+296S L.F.PRESCOTT
+loor
+E
+0n
+.0
+a)0._
+CE
+-a
+E
+m
+C)
+cu
+p0._
+0
+a)
+CL
+0
+0
+xa)
+ ._
+EC
+501F
+20F
+10F
+5p-
+2
+0 2 4 6 8 10 12
+Timeafteradministration(h)
+Figure7 Meanurinaryexcretionratesofparacetamol
+(@)anditssulphate(0),glucuronide(0),cysteine(A)
+andmercapturicacidconjugates(*) (expressedas
+paracetamolequivalents)ineighthealthysubjectsafter
+anoraldoseof20mg/kg.
+withthoseafterintravenousinjection(Figure6).
+Meansystemicavailabilityofparacetamolcalculated
+fromtherelativeareasundertheintravenousand
+oralplasma-concentration-timecurvesis7607.
+Similarresultshavebeenreportedbyothers,andthe
+'first-pass'metabolismofparacetamolmaybedose-
+dependentandinducible(Rawlinsetal.,1977;
+Perucca&Richens,1979).
+Theurinaryexcretionofparacetamolandits
+sulphate,glucuronide,cysteineandmercapturicacid
+conjugatesinhealthysubjectsgivenanoraldoseof
+20mg/kgisshowninFigure7.Whenthedataare
+plottedas'sigma-minus'values(Cummingsetal.,
+1967),theregressionlinesbecomeapproximately
+parallelafter3-4hours.
+Phenacetin
+Phenacetin(acetophenetidine)ishighlylipid-soluble
+withlimitedaqueoussolubility,anditsoral
+absorptionishighlydependenton formulation
+factorssuchasparticlesize(Prescott,Steel&Ferrier,
+1970).Thedrugisextensivelymetabolizedandless
+than0.5%ofadoseisrecoveredunchangedinthe
+urine.Themajormetabolicrouteis0-dealkylation
+toparacetamol(60-80%o),andminorpathwaysincludedeacetylationandhydroxylationtoformp-
+phenetidine,2-hydroxyphenetidine,2-and3-
+hydroxyphenacetinandN-hydroxyphenacetin.These
+metabolites,togetherwiththepreviouslymentioned
+metabolitesofparacetamol,areexcretedlargelyas
+conjugatesintheurine(Brodie& Axelrod,1949;
+Jagenburg&Toczko,1964;Buch,Pfleger,Rummel,
+Ullrich,Hey& Staudinger,1967;Prescott,1969;
+Raaflaub& Dubach,1969;Nery,1971;Uehleke,
+1973;Smith&Timbrell,1974;Klutchetal.,1978).
+Thereisextensive'first-pass'metabolismof
+phenacetinbythesmallintestinalmucosaandliver,
+whichisinduciblebypolycyclichydrocarbonsand
+cigarettesmoking(Kuntzman,Pantuck,Kaplan&
+Conney,1977).Thehydroxylationofphenacetinis
+undergeneticcontrolandtherearemarkedspecies
+differencesinthemetabolismofthedrug(Smith&
+Timbrell,1974).Inanimalsandinman thede-
+acetylationofphenacetinisdose-dependentwitha
+markedrelativeincreaseintheproductionofp-
+phenetidineand2-hydroxyphenetidineathigher
+doses(Raaflaub&Dubach,1969;Smith&Timbrell,
+1974).Theplasmahalf-lifeofphenacetininmanis
+about1h(Prescott,Sansur,Levin&Conney,1968;
+Table2 Pharmacokineticvariablesinfourhealthyadultmalesgivenparacetamol
+12mg/kgintravenouslyandorallyonseparateoccasions.
+Orally
+Eliminationhalf-life(h)
+Distributionhalf-life(h)
+Totalbodyclearance(mlkg-'min-')
+VD,(ml/kg)
+VD,,(ml/kg)
+AUCoougml'h-')Systemicavailability
+1.97+0.3
+28.0+5.8
+76+13%
+Intravenously
+1.98+0.3
+0.13+0.05
+5.45+0.2
+509+68
+897+94
+36.7±+1.2
+Valuesgivenaremean±s.d.VDC,Volumeofcentralcompartment.
+VD,Volumeofcentralandperipheralcompartments.
+I I~~~~1
+METABOLISMOFPARACETAMOL &PHENACETIN 297S
+Kuntzmanetal.,1977).
+Thetoxicityofphenacetinisrelatedtoits
+metabolism.Methaemoglobinaemiahasbeen
+attributedtotheformationofp-phenetidineandN-
+hydroxymetabolitesandisincreasedbymicrosomal
+enzyme induction(Uehleke,1973).Like
+paracetamol,phenacetinisconvertedtoareactive
+alkylatingmetabolitewhichbindscovalentlyto
+hepaticandrenaltubularcellproteinscausing
+necrosis(Mitchelletal.,1977).Thereactive
+metaboliteisprobablyabenzoquinone-iminederived
+fromN-hydroxyphenacetin(Nery,1971;Calder,
+Creek,Williams,Funder,Green,Ham & Tange,
+1973).
+Phenacetinhasbeenuniversallyanduncritically
+implicatedinthedevelopmentoftumoursofthe
+renalpelvis,uretersandbladderinpatientswith
+analgesicnephropathy.Althoughchronictoxicity
+studiesofphenacetinhavefailedtoproducesimilar
+tumoursinanimals,manycarcinogenicaromatic
+aminesareactivatedbyN-hydroxylationandrecent
+studieshaveshownthattheN-O-sulphateand
+glucuronideconjugatesofN-hydroxyphenacetinare
+potentalkylatingagents(Mulder,Hinson&Gillette,
+1977;1978).Theseunstableconjugatesare
+concentratedintheurineandliabletoenzymic
+hydrolysisbytheuroepitheliumandpossibly
+bacteria.Unlikeitspolarmetabolites,phenacetinis
+extensivelyre-absorbedbytherenaltubules.Thereis
+no significantcorticomedullaryconcentration
+gradientandtheratioofurinetoplasmaconcentra-
+tionsisessentiallyunity(Duggin&Mudge,1976).
+References
+ADRIAENSSENS,P.I.&PRESCOTT,L.F.(1978).Highper-
+formanceliquidchromatographicestimationofpara-
+cetamolmetabolitesinplasma.Br.J.clin.Pharmac.,
+6,87-88.
+ANDREWS,R.S.,BOND,C.C.,BURNETT,J.,SAUNDERS,A.&
+WATSON,K.(1976).Isolationandidentificationof
+paracetamolmetabolites.J.Int.med.Res.,4,suppl.4,
+34-39.
+LOSOWSKY,M.S.(1979).Thegastrointestinalabsorption
+ofparacetamolintherat.J.Pharm.Pharmac.,31,
+157-160.
+BRIANT,R.H.,DORRINGTON,R.E.,CLEAL,J.&WILLIAMS,
+F.M.(1976).Therateofacetaminophenmetabolismin
+theelderlyandtheyoung.J.Am.GeriatricSoc.,24,
+359-361.
+BRODIE,B.B.& AXELROD,J.(1949).Thefateofaceto-
+phenetidin(phenacetin)inmanandmethodsforthe
+estimationofacetophenetidinanditsmetabolitesin
+biologicalmaterial.J.Pharmac.exp.Therap.,97,
+58-67.
+BOCH,H.,PFLEGER,K.,RUMMEL, W.,ULLRICH,V.,
+HEY,D.&STAUDINGER,.H.(1967).Untersuchungen
+uberdenoxydativenStoffwechseldesPhenacetinsbei
+derRatte.Biochem.Pharmac.,16,2247-2256.
+CALDER,I.C.,CREEK,M.J.,WILLIAMS,P.J.,FUNDER,
+C.C.,GREEN,C.R.,HAM, K.N.& TANGE,J.D.(1973).
+N-Hydroxylationofp-Acetophenetidideasafactorin
+nephrotoxicity.J.med.Chem.,16,499-502.
+CLEMENTS, J.A.,HEADING, R.C.,NIMMO, W.S.&
+PRESCOTT,L.F.(1978).Kineticsofacetaminophen
+absorptionandgastricemptyinginman.Clin.Pharmac.
+Ther.,24,420-431.
+CLEMENTS,J.A.& PRESCOTT,L.F.(1976).Datapoint
+weightinginpharmacokineticanalysis:intravenous
+paracetamolinman.J.Pharm.Pharmac.,28,707-709.
+CUMMINGS,A.J.,KING,M.L.& MARTIN,B.K.(1967).
+A kineticstudyofdrugelimination:theexcretionof
+paracetamolanditsmetabolitesinman.Br.J.Pharmac.
+Chemother.,29,150-157.
+DUGGIN,G.G.& MUDGE,G.H.(1975).Renaltubular
+transportofparacetamolanditsconjugatesinthedog.
+Br.J.Pharmac.,54,359-366.
+DUGGIN,G.G.&MUDGE,G.H.(1976).Phenacetin:renal
+tubulartransportandintrarenaldistributioninthedog.
+J.Pharmac.exp.Ther.,199,10-16.
+FORREST,J.A.H.,ADRIAENSSENS,P.1.,FINLAYSON,N.D.C.
+& PRESCOTT,L.F.(1979).Paracetamolmetabolismin
+chronicliverdisease.Eur.J.clin.Pharmac.,15,427-431.
+FORREST,J.A.H.,FINLAYSON,N.D.C.,ADJEPON-YAMOAH,
+K.K.&PRESCOTT,L.F.(1977).Antipyrine,paracetamol,
+andlignocaineeliminationinchronicliverdisease.Br.
+med.J.,1,1384-1387.
+GALINSKY,R.E.,SLATTERY,J.T.&LEVY,G.(1979).Effect
+ofsodiumsulphateonacetaminopheneliminationbyrats.
+J.pharm.Sci.,68,803-805.
+GAZZARD,B.G.,FORD-HUTCHINSON,A.W.,SMITH,M.J.H.
+&WILLIAMS,R.(1973).Thebindingofparacetamolto
+plasmaproteinsofmanandpig.J.Pharm.Pharmac.,
+25,964-967.
+HEADING,R.C.,NIMMO,J.,PRESCOTT,L.F.& TOTHILL,
+P.(1973).Thedependenceofparacetamolabsorptionon
+therateofgastricemptying.Br.J.Pharmac.,47,
+415-421.
+JAGENBURG,O.R.&TOCZKO,K.(1964).Themetabolism
+ofacetophenetidine.Isolationandcharacterizationof
+S-(l-acetamido-4-hydroxyphenyl)-cysteine,ametabolite
+ofacetophenetidine.Biochem.J.,92,639-643.
+JONES,D.P.,SUNDBY,G.-B.,ORMSTAD,K.&ORRENIUS,S.
+(1979).Useofisolatedkidneycellsforstudyofdrug
+metabolism.Biochem.Pharmac.,28,929-935.
+JOSTING,D.,WINNE,D.&BOCK,K.W.(1976).Glucuronida-
+tionofparacetamol,morphineandl-naphtholintherat
+intestinalloop.Biochem.Pharmac.,25,613-616.
+KLUTCH,A.,LEVIN,W.,CHANG, R.L.,VANE,F.&
+CONNEY,A.H.(1978).Formationofa thiomethyl
+metaboliteofphenacetinandacetaminophenindogs
+andman.Clin.Pharmac.Therap.,24,287-293.
+KUNTZMAN,R.,PANTUCK,E.J.,KAPLAN,S.A.&CONNEY,
+A.H.(1977).Phenacetinmetabolism:Effectofhydro-
+carbonsandcigarettesmoking.Clin.Pharmac.Therap.,
+298S L.F.PRESCOTT
+22,757-764.
+LEVY,G.,KHANNA, N.N.,SODA,D.M.,TSUZUKI,0.&
+STERN,L.(1975).Pharmacokineticsofacetaminophen
+inthehumanneonate:formationofacetaminophen
+glucuronideandsulfateinrelationtoplasmabilirubin
+concentrationandd-glucaricacidexcretion.Pediatrics,
+55,818-825.
+LEVY,G.&YAMADA,H.(1971).Drugbiotransformation
+interactionsinmanIII:acetaminophenandsalicylamide.
+J.pharm.Sci.,60,215-221.
+McGILVERAY,I.J.&MATTOK,G.L.(1972).Somefactors
+affectingtheabsorptionofparacetamol.J.Pharm.
+Pharmac.,24,615-619.
+MILLER,R.P.,ROBERTS,R.J.& FISCHER,L.J.(1976).
+Acetaminopheneliminationkineticsinneonates,
+children,andadults.Clin.Pharmac.Therap.,19,
+284-294.
+MITCHELL,J.R.,JOLLOW,D.J.,POTTER,W.Z.,DAVIS,
+D.C.,GILLETTE,J.R.&BRODIE,B.B.(1973).Acetamino-
+phen-inducedhepaticnecrosis.I.Roleofdrugmeta-
+bolism.J.Pharmac.exp.Therap.,187,185-194.
+MITCHELL,J.R.,McMURTRY,R.J.,STATHAM,C.N.&
+NELSON,S.D.(1977).Molecularbasisforseveraldrug-
+inducednephropathies.Am.J.Med.,62,518-526.
+MITCHELL,J.R.,THORGEIRSSON,S.S.,POTTER,W.Z.,
+JOLLOW,D.J.& KEISER,H.(1974).Acetaminophen-
+inducedhepaticinjury:Protectiveroleofglutathionein
+manandrationalefortherapy.Clin.Pharmac.Therap.,
+16,676-684.
+MULDER,G.J.,HINSON,J.A.& GILLETTE,J.T.(1977).
+GenerationofreactivemetabolitesofN-hydroxy-
+phenacetinbyglucuronidationandsulfation.Biochem.
+Pharmac.,26,189-196.
+MULDER,G.J.,HINSON,J.A.& GILLETTE,J.R.(1978).
+ConversionoftheN-O-glucuronideandN-O-sulfate
+conjugatesofN-hydroxyphenacetintoreactiveinter-
+mediates.Biochem.Pharmac.,27,1641-1649.
+NELSON,E.&MORIOKA,T.(1963).Kineticsofthemeta-
+bolismofacetaminophenbyhumans.J.pharm.Sci.,
+52,864-868.
+NERY,R.(1971).Somenewaspectsofthemetabolismof
+phenacetinintherat.Biochem.J.,122,317-326.
+NIMMO,J.,HEADING,R.C.,TOTHILL,P.& PRESCOTT,
+L.F.(1973).Pharmacologicalmodificationofgastric
+emptying:effectsofpropanthelineandmetoclopromide
+onparacetamolabsorption.Br.med.J.,1,587-589.
+NIMMO,W.S.,HEADING,R.C.,WILSON,J.,TOTHILL,P.
+&PRESCOTT,L.F.(1975).Inhibitionofgastricemptying
+anddrugabsorptionbynarcoticanalgesics.Br.J.clin.
+Pharmac.,2,509-513.
+NIMMO,W.S.&PRESCOTT,L.F.(1978).Theinfluenceof
+postureon paracetamolabsorption.Br.J.clin.
+Pharmac.,5,348-349.
+0IE,S.,LOWENTHAL,D.T.,BRIGGS,W.A.& LEVY,G.
+(1975).Effectofhemodialysison kineticsof
+acetaminopheneliminationbyanephricpatients.Clin.
+Pharmac.Therap.,18,680-686.
+PERUCCA,E.& RICHENS,A.(1979).Paracetamoldis-
+positioninnormalsubjectsandinpatientstreatedwith
+antiepilepticdrugs.Br.J.clin.Pharmac.,7,201-206.
+PRESCOTT,L.F.(1969).Themetabolismofphenacetininpatientswithrenaldisease.Clin.Pharmac.Therap.,
+10,383-394.
+PRESCOTT,L.F.(1974).Gastrointestinalabsorptionof
+drugs.Med.Clin.N.Am.,58,907-916.
+PRESCOTT,L.F.,ILLINGWORTH,R.N.,CRITCHLEY,
+J.A.J.H.,STEWART,M.J.,ADAM,R.D.&PROUDFOOT,
+A.T.(1979).IntravenousN-acetylcysteine- thetreat-
+mentofchoiceforsevereparacetamolpoisoning.Br.
+med.J.,2,1097-1100.
+PRESCOTT,L.F.,SANSUR,M.,LEVIN,W.& CONNEY,
+A.H.(1968).Thecomparativemetabolismofphenacetin
+andN-acetyl-p-aminophenolinman,withparticular
+referencetoeffectsonthekidney.Clin.Pharmac.
+Therap.,9,605-614.
+PRESCOTT,L.F.,STEEL,R.F.& FERRIER,W.R.(1970).
+Theeffectsofparticlesizeon theabsorptionof
+phenacetininman.Clin.Pharmac.Therap.,11,
+496-504.
+PRESCOTT,L.F.& WRIGHT,N.(1973).Theeffectsof
+hepaticandrenaldamageonparacetamolmetabolism
+andexcretionfollowingoverdosage.A pharmaco-
+kineticstudy.Br.J.Pharmac.,49,602-613.
+RAAFLAUB,H.&DUBACH,U.C.(1969).Dose-dependent
+changeinthepatternofphenacetinmetabolisminman
+anditspossiblesignificanceinanalgesicnephropathy.
+Klin.Wschr.,47,1286-1287.
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+Pharmacokineticsofparacetamol(acetaminophen)after
+intravenousandoraladministration.Eur.J.clin.
+Pharmac.,11,283-286.
+SLATTERY,J.T.&LEVY,G.(1979).Acetaminophenkinetics
+inacutelypoisonedpatients.Clin.Pharmac.Therap.,
+25,184-195.
+SMITH,R.L.&TIMBRELL,J.A.(1974).Factorsaffectingthe
+metabolismofphenacetin.I.Influenceofdose,chronic
+dosage,routeofadministrationandspeciesonthe
+metabolismof[1-14C-acetylJphenacetin.Xenobiotica,
+4,489-501.
+UEHLEKE,H.(1973).Biochemicalpharmacologyandtoxi-
+cologyofphenacetin.InInternationalSymposiumon
+ProblemsofPhenacetinAbuse.Ed.Haschek,H.Pp.
+31-44.Vienna:FactaPublication.

papers/7983238.md

@@ -0,0 +1,16 @@
+# Human pharmacokinetic study of immediate-release (codeine phosphate) and sustained-release (codeine Contin) codeine.
+
+C J Band, P R Band, M Deschamps, J G Besner, A J Coldman
+
+*Journal of clinical pharmacology* (1994)
+
+PMID: 7983238
+DOI: 10.1002/j.1552-4604.1994.tb04008.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+The authors compared, in a double-blind, randomized, crossover study in 13 healthy adult volunteers, the single- and multiple-dose pharmacokinetics, relative bioavailability, and side effects of a new oral sustained-release formulation of codeine (SRC) containing 150 mg codeine base, with oral immediate-release codeine phosphate (IRC). Sustained-release codeine was given at a dose of 150 mg every 12 hours for 5 doses; IRC was given at a dose of 60 mg (2 x 30 mg) every 4 hours for the first 3 doses, and 30 mg every 4 hours thereafter for 12 doses. Plasma codeine levels were determined using a sensitive and specific high-performance liquid chromatography method and corrected for dose administered and codeine base equivalent. Mean values for single-dose pharmacokinetic parameters for SRC and IRC, respectively, were: Cmax of 217.8 and 138.8 ng/mL; Tmax of 2.3 and 1.1 hours; AUC0-inf of 1202.3 and 1262.4 ng.mL-1.hour-1; and t1/2el of 2.6 hours for both formulations. Their respective mean steady-state pharmacokinetic parameters were: Cmax of 263.8 and 222.9 ng/mL; Tmax of 3.2 and 1.1 hours; AUC0-12h of 1576.4 and 1379.1 ng.mL-1.hour-1; and t1/2el of 2.8 and 2.3 hours. These results indicate comparable bioavailability between both formulations with SRC providing delayed peak plasma levels. The sustained-release character of SRC can be explained by a delayed absorption, which is not limiting to drug elimination. Sustained-release codeine provides higher plasma codeine levels over a broader time interval and is expected to improve pain management.

papers/7983238.pdf

@@ -0,0 +1,3 @@
+version https://git-lfs.github.com/spec/v1
+oid sha256:afa51df4a4fba69eebc0f019b34edb332b98296809b66e7a07d0bb833abe7574
+size 213864

papers/PKDB00021.md

@@ -0,0 +1,16 @@
+# Pharmacokinetics/pharmacodynamics of acetaminophen analgesia in Japanese patients with chronic pain.
+
+Shigeo Shinoda, Takahiko Aoyama, Yukio Aoyama, Sachiko Tomioka, Yoshiaki Matsumoto, Yoko Ohe
+
+*Biological & pharmaceutical bulletin* (2007)
+
+PMID: 17202677
+DOI: 10.1248/bpb.30.157
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+Acetaminophen (APAP) is a popular analgesic. In the present study, we characterized the pharmacokinetics and pharmacodynamics of APAP in the Japanese. Five healthy volunteers were administered 1000 mg of APAP orally. Five patients with chronic pain were administered the optimal oral dose of APAP ranging from 600 to 1000 mg to allow for an adequate analgesic effect. Plasma APAP and APAP metabolite concentrations were measured in the volunteers, plasma APAP concentrations and pain scores using a visual analog scale were measured in the patients with chronic pain. Patient data were fitted to a first-order absorption one-compartment model with delayed effects accounted for by an effect compartment. A sigmoid Emax model was used as the pharmacodynamic model. Acetaminophen-cysteine metabolites, which are conjugates of the toxic metabolite N-acetyl-p-benzoquinone-imine, were detected in the plasma at levels lower than 0.2 microg/ml, but no side effects were observed. The pharmacokinetic and pharmacodynamic parameter (mean+/-S.D.) estimates were as follows: clearance, 18.7+/-4.7 l/h; distribution volume, 30.9+/-6.8 l; absorption rate constant, 2.4+/-1.3 h(-1); rate constant for the elimination of APAP from the effect compartment, 1.3+/-0.5 h(-1); maximum pain relief score, 4.6+/-2.2 units; effect compartment concentration at 50% maximum, 2.0+/-1.2 microg/ml; and sigmoid factor, 1.3+/-0.7. These results suggest that these parameters can be used to determine an effective APAP dosage regimen for Japanese patients with chronic pain.

papers/PKDB00021.pdf

@@ -0,0 +1,3 @@
+version https://git-lfs.github.com/spec/v1
+oid sha256:5d624349b137745bfa23bd040632e770565322dcd8e31982207a0f3d62d817c2
+size 658096

papers/PKDB00021.txt

@@ -0,0 +1,631 @@
+Pharmaceutical Society of Japan
+NII-Electronic Library Service
+PharmaceuticalSociety  of  Japan
+January 20e7 Biol. Pharm. BuU, 30(1) t57-161  (2007) 157
+Pharmacokinetics/Pharmacodynamics
+Japanese Patients with  Chronic Painof
+ Acetaminophen  Analgesia in
+Shigeo SHiNoDA," [[bkahiko AoyAMA,h Yukio AoyAMA," Sachiko ToM[oKA,:
+lrbshiaki MMsuMoTo,*'b  and  Ybko OHE"
+"Second
+ Dqpartment of Anesthesiology; foho Uhiyersity School of Medicine; 2-il-6 Ohashi. Meguro-ku, n)lp'o
+J53-8515. mpan.' bDqpartment  of Clinicat Pharmacokinetics, Collage qf Pharmac.v Nihon  Univensit.v,; 7-7-1
+NLtrashinodai, Funahashi, C7iiha 274-8555, j2u]an: and  
+C'Labofatory
+ ofDrug Metabolism and  Pharmacokinetics, S7to}va
+Pharmaceuticat Uhivensity; 3-3i65 Hl'gashi-tamagaveagahaen, Mdchida. Ibig,o i94-S543, Jopan.
+Recejyed July 25, 2006i accepted  October 28, 2006
+   Acetaminophen  (AIAP} is a popular analgesic.  In the present study,  we  characterized  the pharrnacokinetics
+and  pharmacodynamics  of ARAP  in the Japanese, Five healthy volunteers  werc  administered  1000 mg  of ARAP
+orally.  Five patients with  chronic  pain were  administered  the optimal  orat  dose of APAP  ranging  from 600 to
+1000mg  to allow  for an  adequate  analgesic  effect.  Plasma  ARAP  and  A2AP  metabolite  concentrations  were
+measured  in the volunteers,  plasma ARAP  concentrations  and  pain scores  using  a  visual  analog  scale were  meas-
+ured  in the patients with  chronic  pain. Patient data were  fitted to a  first-order abserption  one-compartment
+model  with  delayed effects  accounted  for by an  efTect  compartment.  A  sigmoid  E... model  was  used  as the phar-
+macodynamic  model.  Acetaminophen-cysteine metabolites,  which  are  conjugates  of  the toxic metabolite  IVL
+acetylzp-benzoquinone-imine,  were  detected in the plasma  at levels lower thfin O.2 pgiml, but no  side  effects  were
+obseryed.  The  pharmacokinetic and  pharmacodynamic  parameter (mean± S.D.) estimates  were  as  fo11ows: clear-
+ance,  18.7± 4.7Vh;  distribntion volume,  30.9± 6.81; absorption  rate  constant,  2.4± t.3 hJi; rate  censtant  for the
+elimination  ofAIzaP  t'rom the effect  compartment,  1.3± O.5 h-i; maximum  pain relief  score,  4.6± 2.2 units;  efTect
+compartment  concentration  at 50%  maximum,  2.0± 1.2pglml; and  sigmoid  facto4 1.3± O.7. These results  sug-
+gest that these parameters can  be llsed  to determine an  effective  AIAP  dosage regimen  for Japanese patients
+with  chronic  pain.
+   Ke}' words  acetaminophen;  pharmacokinetic-pharmacodynamic  modeling;  chronic  pain
+  Acetaminophen (ARI{P) is a  popular analgesic  world-
+wide,  but in Japan, AIzaP  is used  mainly  as  an  antipyretic  in
+children.  ARAP  is rarely  used  as  an  analgesic  in Japan, be-
+cause  the recommended  dosage of  ARAP  in Japan (less than
+1500mgfd)i) is lower than that in United States (less than
+4000mgld).2}
+  ARPLP is metabolized  by UDP-glucuronosyltransferase,
+sulfotransferase  and  cytochrome  P450 (Fig. 1). There is sub-
+stantial interindjvidual variability in APAP  glucuronidation,3}
+and  polymorphisms of  UDP-glucuronosyltransferase have
+been reported.4'5)  APAP  is metabolized  by cytochrome  P450
+NHCOCH3
+osovAS
+NCOCHI
+oNAPQI
+ SULTe
+CYP2El
+ GST-
+NHCOCH3
+OHAPAP
+ UGT-
+NHCOCH,
+OH
+-SG
+NHCOCH:
+e'CeHgOGAG
+NHCOCH:
+OHAC
+Cvs
+Fig. 1. Mctabolismot'Acetarninophen
+ Atetarninophen  is metabolized  by cy{ochreme  P4SU 2F.1 to thc texic metubu[itc  ,N'-
+acetyl-p-benzDguinonc-iminc,  "'hich  is coajuguLed  by glutathione to cysteine  metabo-
+lites. APAP; acctaminophcn,  AS; acetuininophen  sulfate, AG; acetaminophen  glu-
+curonide,  NAPQI;  "Lacetyl-p-bcnzoquinune-imine, AC; acetaminophen  cysteine
+metubolites.  SUIJ/ sulfotransferase,  LJGT/ UDP-glucuronosyltransferasc. GST/ glu-
+tathinneS-transferase,CIYP2El;c)tocliromcP45e2El.
+*  Tb whom  correspondence  should  bc addressed.
+2El to the toxic metabolite  IVLacetyl:p-benzoquinone-imine
+(NAPQI). The  genotype frequency of  cytochrome  P450  2E1
+differs with  ethnicity.6)  The degree of  chlorzoxazone  clear-
+ance,  which  is uscd  as a phenotypic probe of  CYP2El  en-
+zyme  activity in Japanese, is lower in Caucasians.i) There-
+fbre, the pharmacokinetics of  AIAP  in high doses in Japan-
+ese  patients needs  to be clarified  to determine whether  the
+use  ofARAP  as an  analgesic  is safe,
+  The relationship  between pain relief  and  ARAP  concentra-
+tion has been investigated {n German8) and  Danish9) postop-
+erative  patients. In children  undergoing  adenotensillectomM
+the pharmacokinetic-pharmacodynamic model  has been de-
+scribed.TO)  However,  pain sensitivity differs among  ethnic
+groups.i i) A  better understanding  of  the dose-effect retation-
+ship  in Japanese is needed  to control  chronic  pain. There are
+no  data describing the pharmacokinetics and  pharmacody-
+namics  of  AI\tP  and  its metabolites  in the Japanesc. An un-
+derstanding of  the relationship  between the analgesic  effect
+and  the time after ARAP  administration  is important fbr de-
+termining the dosage of  ARAP  for the treatment  of  ehronic
+pain, The aims  of  this study  are  to characterize  the pharma-
+cokinetics  and  pharmacodynamics of  ARAP  and  to determine
+an effective  ARAP  regimen  in Japanese patients with  chronic
+pain.
+MAI'ERIALS  AND  METHODS
+  Materials  APAR  acetaminophcn  glucuronide (AG),
+theophylline.  ammonium  acetate, and  perchloric acid  were
+obtained  from Sigma Chemical CSt. Louis, MO,  U.S.A.). Ac-
+etaminophen  sulfatc  (AS) and  acetaminophen-cysteine  (AC)
+e-mail]matsuy@pha.nihon-u.ae.jp C  2007 Pharmaceuticul Society c}fJupan
+NII-Electronic  
+Pharmaceutical Society of Japan
+NII-Electronic Library Service
+PharmaceuticalSociety  of  Japan
+158 Xlo1. 30, No.  1
+Table 1. Patients' ChaTacteristics
+PatientID 't 2 3 4 s Mean S,D.
+Malei'female
+Age  (years)
+Weight(kg)
+AST  (IU/1)
+ALT  (IUII)
+Ser(mgldl)
+F745524141  FS4521611
+ O.6
+ FS8743552
+ o.s
+F4051164
+ O.6
+M497e19231
+S56e2221
+ O.7
+131181902
+AST;aspartatearninoLransferase.AIIr;alanincaminotrunsferasc.Scr;senimcreatinine.
+were  donated by Showa Yakuhin Kako (Tokyo, Japan). All
+chemicals  and  reagents  were  of  analytical  or chromato-
+graphic grade.
+  Study Design Five healthy volunteers  and  five patients
+with  chronic  pain who  were  not  using  any  other  analgesics
+were  included in this study  after giving infbrmed consent.
+The study  protocol was  approved  by the ethics  review  com-
+mittee  of  Toho University Ohashi Medical Centen The pa-
+tients' characteristics  are  shown  in Table 1. None  ofthe  pa-
+tients presented with  major  renal  or  hepatic impairment,
+  The five healthy volunteers  received  1000mg  of  AIipLP
+orally.  The  volunteers  fasted from after  their last meal  on  the
+day preceding ARAP  administration  to 3h after AR4P  ad-
+ministration.  A  cannula  was  inserted into an  antecubital  vein
+to facilitate the sampling  of  vcnous  blood. Blood was  ob-
+tained  befbre A}AP  administration  and  15. 30, and  45 min,
+and  1, 2, 3, 4, and  6h after the administration.  After centrifu-
+gation (3000rpm, 10min), plasma samples  were  stored  at
+-30  
+OC
+ until assayed.
+  The study  of  the five patients with  chronic  pain was  di-
+vided  into two phases. In the first phase, we  determined the
+optimal  dose that al]ows  for an  adequate  analgesic  efTect  of
+ARAP  (Ca]onalrt', Showa Yakuhin Kako). Each patjent re-
+ceived  an escalating  oral dose until an  apparent  effbct of
+ARAP  analgesia  was  observed,  The  upper  limit of  the ARALP
+dose was  1000mg  as  a  single dose and  3000mg as a daily
+dose, In the second  phase, each  patient was  administered
+ARAP  tahlets at thc optima]  dose deterrnined in the first
+phase with  200ml  water.  The patients fasted from after their
+last meal  on  the day preceding ARAP  administration  to 3h
+after  AI}AP  administration.  A  cannula  was  inserted into an
+antccubital  vein  to facilitate the sampling  of  venous  blood.
+Blood  was  obtained  before ARAP  administration  and  15, 30,
+and  45 min,  and  l, 2, 3, 4, and  6h after the administration.
+Chronic pain was  assesscd  using  a visual  analog  scale  (VAS;
+O=no  pain, 10=worst pain imaginable). Pain scores  werc
+recorded  at every  blood sampling.  Pain relief scores  were  ob-
+tained  by subtracting  the pain score  from the initial pain
+score. After centrifugation  (3000rpm, 1Omin), plasma  sam-
+ples were  storcd  at -30 
+OC
+ until  assaycd.
+  Acetaminophen Assay  Tb study  thc healthy volunteers,
+APAR  AG, AS, and  AC  concentrations  were  determined
+using  the modified  high performance liquid chromatography
+(HPLC) method  described by Brunner  and  Bai.i2) The
+plasma samples  were  deproteinated by adding  of  6%  (v/y)
+perchloric acid  in water  containing  theophylline  as an  inter-
+nal  standard.  The  samples  were  rnixed  using  a vertex  fbr 5 s
+and  then centrifuged  (14000rpm, 10min, centrifuge  5417R,
+EppendorD. The  supernatant  was  iTijected into the HPLC
+system.  HPLC  was  perfbrmed  using  a CAPCELL  IIAK CI8
+column  (4.6mmX150mm, Shiscido) by isocratic elution
+with  a mobile  phase of  10mM  ammonium  acetate (pH
+6,O)-acetenitrile (95 :5, vfv) and  ultraviolet detection (SPD-
+10A, Shimadzu) at 254nm. The flow rate was  O.8mVmin.
+The concentrations  of  the metabolites  were  calculated  as
+ARAP  equivalents.  In the study  of  the patients with  chronic
+pain, APAP  concentration  was  determined by fluorescence
+polarization immunoassay at  Mitsubishi Kagaku Bio-Clinical
+Laboratories (Tbkyo, Japan).
+  Data Analysis To study  both the volunteers  and  the pa-
+tients, noncompartmentai  ana}ysisi3} using  the WinNonlin
+pharmacokinetic software  package (Pharsight Corporation,
+Mountain View, CA, U,S,A,) was  perfbrmed to determine the
+pharmacokinetic parameters. The area under  the concentra-
+tion-time curves  (AUO was  extrapolated  to infinity fbr
+AIIAP and  its metabolites.  The peak APAP  concentration
+(C.,,) and  the time to reach  CL.,. (7L,..) were  obtained  di-
+rectly from the raw  data. 
+'fo
+ study  the patients with  chronic
+pain, a first-order absorption  one-compartment  model  with
+delayed effects accounted  for by an  effect compartment  was
+used.i4} The model  was  parameterized in terms ofthe  absorp-
+tion rate  constant  (k,), apparent  volume  of  distribution (Pli),
+total clearance  (CL) after oral administration,  and  the rate
+constant  for the elimination  of  AfXP  from the eifect com-
+partment (k,.). APAP  was  administered  orallM  and  CL  and  Vh
+were  cenfbunded  by bioavailability. The pharmacodynamic
+model  was  used  as  a  sigmoid  E.,. model  according  to the
+equatlon:E=(E.,.XCe7)ICECsor+CeT),
+where  E, E.,., Ce, ECso and  7 represent  the pain relief score,
+the maximum  pain relief score, the ARAP  concentration  in a
+hypothetical efTect  compartment,  the AR"LP Ce that corre-
+sponds  to 50%  of  the E..., and  the sigmoid  factor, respec-
+tively. The  fitting process was  a  simultaneous  estimation  by a
+nonlinear  least squares  fit of  the model  to the AIVLP concen-
+tration and  the pain relief  score  profiles using  the WinNonlin
+pharmacokinetic software  package (Pharsight Corporation,
+Mountain  ViewL CA, U.S.A.),
+  Simulatien Using PharmacokineticlPharmacodynamic
+Parameter Estimates Using mean  pharmacokinetic and
+pharmacodynamic parameters, simulations  were  perfbrmed
+to predict the time  course  of  A}AP  efTects  fbr oral  doses
+ranging  from 250 to 4000rng with  a varied  dosage regimen.
+For each  simulation,  a summary  parameter, namely,  the efi
+fective time during which  the pain relief score  was  higher
+than three VAS  units, was  used  to characterize  the time
+course  ofeach  endpoint  after AIIAP administration,
+NII-Electronic  
+Pharmaceutical Society of Japan
+NII-Electronic Library Service
+PharmaceuticalSociety  of  Japan
+january 2007 159
+A3U
+:.I'an-
+ 20･e-g:8S
+ 107?
+oo123411n=(h)s67
+B30)cgV
+ lo･!E-5･2z2
+ io1.Eijoo1
+Fig. 2. ARAP  (A) and  Metabolites (B) ConcentTations in Five Healthy Nblunteers
+ TheconcentraLiensofthcmetaboliteswerecateulatedasAPAPcquivalents.PTotsreprcsentrnean± S.D,
+2341'1]re{h)561
+r.
+2
+t
+o
+.?tHiJ-:eEzzUrf
+Tablc 2. NoncoTnpartmental Analysis for ARAP  in Healthy Nlolunteers
+NblunteerlD 1 2 3 4 5 Mcan S.D.
+ARptP
+ACAGAS
+Ab(](pg'h/ml}
+Liny1)CL,,F(1/h)
+C.,. (slglml)
+71naN (h)AUC(ug･blml)
+AUC(ltg･h,ml)
+.4UC(ug･h/ml)
+96.566.411,421.S
+ O.25
+ 4,O5323.0
+68.eS2,613,920.0
+ o.s
+ 1,O6911,6
+s7.g79.415,414.4
+ O.5
+ 6.06422.6
+72.252.910.4182
+ O.5
+ 3.85319.0
+64.797.414.714,2
+ O.5
+ 3.6902g.g
+77,869.713217,7
+ e.s
+ 3J6621,e
+13.7l9.0223,3o.t
+ 1.8156,3
+Dose/  1000  mg.
+RESUI:TS
+  The concentrations  ofAPAP  and  its metabolites  in healthy
+volunteers  are shown  in Fig. 2. 
+rlable
+ 2 shows  the AUC  values
+of  ARAP  and  its metabolites.  The AUC  for AC  was  small
+corrrpared  with  those for other  metabolites.  No  side effects
+were  observed  in the healthy volunteers.
+  In the patients with  chronic  pain, the optimal  mean  (range)
+ARAP  dose that allowed  for an  adequate  analgesic  effect  of
+AIIAP was  800 (60or1000) rng  as a  single  dose. The AReLP
+concentrations,  pain scores, and  pain relief  score  profiles are
+shown  in Fig. 3. The APAP  concentrations  reached  the maxi-
+mum  concentration  30min after drug administration  in four
+patients. In those four patients, the pain score  decreased
+maximally  45min after drug administration.  The  effects of
+ARAP  were  delayed compared  with  the APAP  concentra-
+tions. In the other  patient, the APAP  concentration  increased
+until  2 h after administration.  The pain score  decreased rnaxi-
+mally  30min after  administration.  No  side effects were  ob-
+served  in the patients.
+  Plotting pain relief  score  against  AIAP  concentration  re-
+vealed  a counterclockwise  hysteresis relationship  (Fig. 4),
+The individual pharmacokinetic and  pharmacodynamic pa-
+rameters  are shown  in Table 3. Figute 5 shows  the simulated
+relationship  between the daily dose ofAIAP  and  the effec-
+tive time during which  the pain relief scores  were  higher than
+three VAS  units in five dosage schedules.
+DISCUSSION
+  There is few information concerning  the analgesic  effect-
+time relationship  ofARAP  in the Japanese. The characteriza-
+A
+T]Ort
+ 25ot/iE
+ 2o-!i'
+ is
+i io
+l,
+B
+o
+30r-
+ 2s..Edni2ev-:te
+ tsE!s
+ le??5o
+o1?
+APAPcencentratiun
+serber
+3'Vime
+ Ch)4s6
+'----･Painrcliefscore
+1 lo-s
+7
+o113Time{h)456T
+6e.
+  ･t4g2o
+Le
+s
+  u(i
+ g
+  ,:
+  s-
+  ua
+  ･s
+  c2
+o
+Fig, 3. ARAP  Concentration and  Pain Score Profiles (A). and  APAP  Con-
+centration  and  Pain Relief Score Profiles (B) in Five Patients with  Chronlc
+Pain
+ Puin relief  scores  werc  obtained  by subtracting the pain score  ftern the initial pain
+scere. The  bold  line and  the bold dashed linc rcpTesent  thc  data ofa  patienl with  a  deiay
+in rhe tirne to reach  the  peak ARALP concentration.  The thin  iines and  thin dashed lines
+representthcotherputients.
+Pharmaceutical Society of Japan
+NII-Electronic Library Service
+PharmaceuticalSociety  of  Japan
+160 Nbl. 30, No, 1
+fabie 3.Phurmacokinetie,'Phartnacodynamic Parameters for APAP  in Chronic Pain Putients
+Patient ID 1 2 3 4 s Mean SD.
+V,,,F{1)Cl'L/F(lih)
+ig(1/h)keo(1/h)EiiaxECso("g/inb
+TDose
+ Cmg)
+ 24,7
+ 16.1
+ 3.48
+ l.]5
+ 6,48
+ 2,34
+ 1.41800
+ 27.0
+ 12,8
+ 3,85
+ O.92
+ 3.84
+ 2.92
+ 1.85600
+ 28,S
+ 18.2
+  1.89
+  O.S3
+  L,99
+  1,56
+  1.971000
+31,721.9
+ 2.06
+ 1.S2
+ 3.44
+ 3.12
+ 1,24800
+ 42.1
+ 24.6
+ O,6]
+ 1.94
+ 7.38
+ O.14
+ {).19800
+ 30.9
+ 18.7
+ 2,4
+ 1.3
+ 4.6
+ 2.0
+ 1.3800
+ 6.8
+ 4.7
+ 1.3
+ o.s
+ 2.2
+ 12
+ O,7114I
+s ,-
+6ustt2-4esE2-
+24
+ISGvy-t
+  T2y-'sLvx6
+oo  --- -･
+ [o lo
+AP.,tPcencei]trallenUlg'mL)
+3e
+Fig. 4. Relationship between AR-LP Concentratien and  Pain Relief' Score
+in Five Paticnts with  Chronic Pain
+ F'lotsrcpTesentmeanva]ues,
+tion ofthe  effect-time  relationship  is usefuI  fbr determining
+a dosage schedule  fbr AII4LR The main  objective  ofour  phar-
+macokinetic  and  pharmacodynamic study  is to characterize
+the pharmacokinctics of  ARAP  and  its metabolites  for a sin-
+gle 1000mg  dose of  AIAP  and  the analgesic  effect-time
+course  of  ARALP after a singlc  high dose in Japanese patients
+wj  th chronic  pain.
+  Hepatotoxicity is a consequence  ofAPAP  overdose  duc to
+the increased metabolism  of  AIAP  through  oxidation,  result-
+ing in an  inerease in NAPQI  concentration.  In case  of  an
+ovcrdosc,  uncoajugated  NAPQI  binds to intracellular hepatic
+macromolccules  to induce cell necrosis  and  damage.i") Be-
+causc  NAPQI  is eonjugated  by glutathione into cysteinc
+metabolites,  the amount  of  such  coajugates  was  considered
+to be a measure  of  the endpoint  of  hepatotoxicity in the
+study.  The  AUC  of  AC  was  on]y  5%  of  that ofAIAP  after  a
+1000mg  dose ofARAP  (Tab]e 2). This value  is almost  equal
+to that reported  by Chan et aLi6)  (5%) in Chinese diabetic pa-
+tients aftcr 20mg/kg body weight  ARAP  adrninistration.
+Prescott et aL  reported  that plasma AC  was  not  detectable
+after  a single  1000mg  dosc of  AIIAP in the healthy volun-
+teers in Scotland i 7) because it was  considered  that ARPLP  was
+scarcely  metabolized  to NAPQI  after  a 1000mg  dose of
+ARAR  TheAUC  values  fbr AG  and  AS  were  almost  equal  to
+those reported  by Prescott et at, i7) The  APAP  glucuronidation
+and  sulfate cotijugation  activity  in the Japanese were  simi]ar
+to those in Caucasians. The  AIipLP concentration  4 h after ad-
+ministration  in this study  was  6.7"glml, while  toxic concen-
+trations higher than 120-300paglml appeared  4h  after ad-
+ministration.iS'T9)  Side effects  were  not  observed  in this study.
+Thcrefore, a  single 1OOO mg  dose ofAPAP  was  considered  to
+o7a
+ t
+            t･
+           t
+           '          '
+         '
+        '
+        r
+       1      '
+      '
+     '
+    t
+    t   1
+  t ''
+  l i
+        -
+ i -
+ l--
+ t.    .i-
+  t "t'  -'--
+tt
+  t
+     -
+  .. 
+J-
+ l ,t/.
+ J,/1
+ tt
+oleoo  2ooe 3ooD 4oeo
+  Dalydesc(ing)
+Fig. S. Relationship between the Daily Dose of  ARAP  and  the Effective
+Timc  ofFive  Dosage  Sehcdules
+ Efi'ective timc  -'as  defined as  the time during which  the pain relief  scores  werc
+highe[ than three VAS  unlts. The dc]sagc schcdutes  we[e  ttom oncc  to fivc timcs a day.
+    ,onceaday/---,twiceaday;.----,3timesadayl  ,4timcsa
+day/--------,5timesaday.
+be a safe  analgesic  dose for theJapanese.
+  Therc were  no  significant  difftrcnces in PCh/F and  CLIF
+ca]culated  by noncompartmental  analysis between the pa-
+tients with  chronic  pain and  the healthy volunteers  (p=O.l2,
+O.11, respectively  by unpaired  t-test, data not  shown).  The
+pharmacokinetics of  ARAP  have been reported  in patients
+with  chTonic  renal  failure,i7) portal hypertension,2e) and
+chronic  tiver disease.2t'22) ln patients with  these diseases, the
+AfPLP  halfiiife was  long compared  with  that in healthy vol-
+unteers.  Patients with  chronic  pain tend  to take analgesics
+over  a long period. Although it is necessary  to note  the effect
+of  these  diseases on  ARAP  pharmacokinetics, in this study
+there  was  no  significant difference in the pharmacokinetics
+of  APAP  between the healthy volunteers  and  the patients
+with  chronic  pain. We  determined that a  single 1OOOrng dose
+of  AEAP  can  be safely  used  for Japanese patients with
+chronic  pain.
+  Because the onset  ofthe  analgesic  efTlect ofAPAP  was  de-
+layed compared  with  the AIIAP eoncentration  and  the coun-
+terclockwise hysteresis relationship  was  observed  we  used  a
+first-order absorption  one-compartment  model  with  delayed
+effects  accounted  fbr by an  effect  compartment.23)  The  hys-
+teresis relationship  represents  an  apparent  temporal  displace-
+ment  between APAP  concentration  and  pain relief The
+APAP  concentration  and  pain reliefprofiles  in Japanese pa-
+tients with  chronic  pain can  be described using  a one-com-
+partment with  an  effect compartment  model.  The pharmaco-
+NII-Electronic  
+Pharmaceutical Society of Japan
+NII-Electronic Library Service
+PharmaceuticalSociety  of  Japan
+January 2007
+kinetic and  pharmacodynamic parameters of  APAP  were  ob-
+tained from data from Japanese patients with  chronic  pain. A
+delayed onset  of  thc effects have been observed  in chil-
+dren.iO'24) ln those studies, the delayed onset  of  the efft)¢ts is
+described by a one-compartment  with  an  effect compartment
+model,  The equilibration  halftimes as an  index of  the dc-
+layed onset  ofthe  effect are 1.3,iO) O.8824)h. The equilibration
+halflt{me in this study  was  O.53 h. Pickering et aL  reported
+that the analgesic  effect  of  AIipLP involves a central seroton-
+crgic  mechanism,  incLuding an indirect interaction of  ARALP
+with  serotonergic  receptors.25)  The  delayed onset  ofthe  effect
+and  thc eountcrclockwise  hysteresis relationship  might  be
+due to this pharmacologic mechanism,
+  Pain control  fbr patients with  chronic  pain requires  contin-
+uous  pain rclief. We  simulated  the effbctive time  during
+whjch  the pain reliefscores  wcre  higher than thrce  XQXS units
+using  pharmacokinctic and  pharmacodynamic parameter es-
+tjmates  (Fig. 5), The time during which  the pain relief scores
+were  higher than  three VAS  units  was  considered  to represent
+thc period ofpain  relief.  The  recommended  dosage in United
+States is le$s than  4000 mg  a day.2) ln Japan, the dosage is al-
+lowed to be increased up  to 3000 mg  a day at a physician's
+discretion. Because  the APAP  glucuronidation and  sulfate
+coajugation  in this study  were  equaL  to those in Cau-
+casians,T7) thc simulations  were  performed for dosages rang-
+ing from 250 to 4000 mg  a day and  each  dosage was  admin-
+istered as eithcr a single dose or divided into 2 to 5 doses.
+The simulation  suggcsts  that the dosage plan (500mgX
+3 times/d), as suggested  by the package insert,i) relieves  pain
+fbr only  1O.2h. Relief from the pain fbr ]6h requires  that the
+daily dose be incrcascd to 2000mg  divided into five doses or
+2400mg  divided into four doses for Japanese patients with
+chronic  pain. These  results  suggest  tbat thc dosage ofARtYP
+needs  to be higher than  that recommended  by the package
+insert for Japancse patients with  chronic  pain. Generally,
+Japanese and  Caueasians standard  body weights  are 60 and
+70kg, respectively. Considcring that the Japanese build is
+smaller  than that of  Caucasians, the dosage of  APAP  fbr
+Japanese patients with  chronic  pain may  need  to be lower
+than  that in Unitcd States. An  aminotransferase  elevations  as-
+sociatcd  with  daily intake of  4000mg  of  AIAP  in healthy
+adults  has been reported.26) An  ARAP  toxicity in the casc  of
+multiple  doses and  higher dosages in the Japanese nced  to be
+invcstigatc using  AC  and  a new  biomarker,2') ophthalmic
+acid  which  indicatcs hepatic glutathione consumption  as an
+ARALP overdose.
+  In conclusion,  we  characterized  the ARALP concentration
+and  pain relicf score  profiles in Japanese patients with
+chronic  pain after a single  high dose of  AIAP  An  under-
+standing  of  the pharmacokinetic and  pharmacodynamic pa-
+rameters  fbr ATIAP  will  allow  fbr an  effective  dosage plan.
+161
+REFERENCES  AND  NOTES
+t) Showa Y]knhin Kako  Co,, Ltd.. Calonal'fi' 
+'fablet
+ Package Insert Re-
+   vised  in May  2005 Csecond edition>.
+2) Physicians' Desk  Referen¢ e. S7th ed.. Thomson  PDR,  2003,
+3) Court M, H., Duan  S. X., Moltke L. L. V, Greenblatt D. J., Patten C. J.,
+   Miners J. O., Mackenzle  R I,, M Pharmacot. Exp, T}fien, 299, 99g-
+   IO06 (200T).
+4) Fqjita K., Ando  Yl, Nagashima  E, Yiimamoto VLC, Endo  H.. Kodama
+   K., Araki K., Miya  T., Narabayashi M., Sasaki Y., Drug  Metab. Phar-
+   macokinet.,  21, 79-81  (2006),
+5) Fujita K.. Ando  Y/, Nagashima  F., ftlamainoto W., Endo H., Kodama
+   K., Araki K., Miya  T., NaTabayashi M., Sasaki Y., Drug  Metab. Phar-
+   macvkinet.,21,75-78(2006),
+6) Belt H. M., Roos R H., Their R., J}it. Afch. Occup. Environ. Uealth,
+   76, 174 -T8S QO03).
+7) Kim  R. B., YUmazaki  H., Chiba K., O'Sea D., Mimura  M., Guengerich
+   E R, Ishizakl T., Shimada  T., Wilkinson G. R., J. Phaf'macol. Exp.
+   Ther.,279,411(1996),
+8} Beck D. H., Schenk M. R., Hagernann K., Doepfhier U. R., Kox W  J,,
+   .4nesth.Analg.,90,43]436(2000).
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+   Rasmussen  S. N,, Rasmusscn  M,,Acta Anaethesiol. Scand., 47, 138-
+   145(2C)O]).
+10) Anderson  B. J., HoLford N. Lt. G., Wool]urd G. A., Kanagasundaram
+   S.,MahadevanM,Anesthesiolqgr?,90,41t421C1999).
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+   (2005}.
+12) Brunner L. J., Bai S.,J Chm)matogn B Biomed. Sci., 732. 323-329
+   {1999).
+13) Chan K. K..Gilbaldi M,,J  Pharm. Biopharm, 1O, S51-558  (1982).
+T4) Sheiner L. B., Stanskj D. R., Vbzeh S., Miller R. D., Ham  J., Clin.
+   Phar,naeol. rvien, 25, 358-371  {1979).
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+   60,241-246(1996),
+l6) Chan  M, T. V, Anderson P. J., Cban J. C. tw., Lau G, S. N., Critchley J.
+   A. J. H.. Eun  J  C'lin. Pharmacol. , 52, 2S5-288  (1997).
+17) Prescott L. E, Speirs G. C., Critchley j. A. J. }T., Tlernple R. M., Win-
+   ney  R. J,, Eum .[ Clin. PhannacoL,  36, 29L- 297 (1989).
+I8) PennaA.,BuchananN.,BnJ  CIin.Pharmacol.,32, 143-149(1991),
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+   ment.  PharmacoL  T7ien , 20, 29-36  {2004),
+21) Forrest J. A. H., Adriaenssens P., Finlayson N. D. C., Prescott L, F.,
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+   Chent,281,]6768-16776(2006),
+NII-Electronic  

papers/PKDB00024.md

@@ -0,0 +1,16 @@
+# The effect of propranolol on paracetamol metabolism in man.
+
+O Z Baraka, C A Truman, J M Ford, C J Roberts
+
+*British journal of clinical pharmacology* (1990)
+
+PMID: 2306420
+DOI: 10.1111/j.1365-2125.1990.tb03631.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+Ten healthy volunteers were treated for 4 days with 160 mg propranolol HCl and placebo in random order. At the end of each treatment salivary antipyrine kinetics and the plasma kinetics and urinary excretion of paracetamol and its major metabolites were measured following a 1500 mg oral dose. Propranolol prolonged the half-life of antipyrine by 11 +/- 5% (mean +/- s.e. mean) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol increased the half-life of paracetamol by 25 +/- 12% (P less than 0.05) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol decreased the partial clearance of paracetamol to its cysteine and mercapturate derivatives by 16 +/- 3% (P less than 0.05) and 32 +/- 7% (P less than 0.05), respectively. The partial clearance to the glucuronide conjugate was decreased by 27 +/- 6% (P less than 0.05), whereas that to sulphate was not changed significantly. Propranolol inhibits paracetamol metabolism predominantly through inhibition of the oxidation and glucuronidation pathways.

papers/PKDB00024.pdf

@@ -0,0 +1,3 @@
+version https://git-lfs.github.com/spec/v1
+oid sha256:cd75a999dd15478d2bda1621d62eeea4cd1d7b899cdc6b364bcf621853252976
+size 589547

papers/PKDB00024.txt

@@ -0,0 +1,333 @@
+Br.J.clin.Pharmac.(1990),29,261-264
+Theeffectofpropranololonparacetamolmetabolisminman
+0.Z.BARAKA.C.A.TRUMAN.J.M.FORD& C.J.C.ROBERTS
+DcpartmcntofMedicine,BristolRoyalInfirmary,BristolBS28HW
+Tenhealthyvolunteersweretreatedfor4dayswith160mgpropranololHClandplacebo
+inrandomorder.Attheendofeachtreatmentsalivaryantipyrinekineticsandtheplasma
+kineticsandurinaryexcretionofparacetamolanditsmajormetabolitesweremeasured
+followinga1500mgoraldose.Propranololprolongedthehalf-lifeofantipyrineby11±
+5%(mean±s.e.mean)andlowereditsclearanceby14±3%(P< 0.05).Propranolol
+increasedthehalf-lifeofparacetamolby25±12%(P<0.05)andlowereditsclearanceby
+14±3%(P< 0.05).Propranololdecreasedthepartialclearanceofparacetamoltoits
+cysteineandmercapturatederivativesby16±3%(P< 0.05)and32±7%(P< 0.05),
+respectively.Thepartialclearancetotheglucuronideconjugatewasdecreasedby27±6%
+(P< 0.05),whereasthattosulphatewasnotchangedsignificantly.Propranololinhibits
+paracetamolmetabolismpredominantlythroughinhibitionoftheoxidationand
+glucuronidationpathways.
+Keywordsdrugmetabolismdruginteractionpropranololparacetamol
+antipyrine
+Introduction
+Sinceparacetamolisoxidisedtoahepatotoxic
+intermediatemetaboliteN-acetylp-benzo-
+quinoneimine(Corcoranetal.,1980;Meredith
+& Goulding,1980),interactionswithdrugs
+thatinducehepaticmono-oxygenases(Mitchell
+etal.,1983;Perucca&Richens,1979;Prescottet
+al.,1981)andthosethatinhibitthem(Mitchellet
+al.,1984;Sanchez-Martinezetal.,1985)areof
+interest.
+Propranololinhibitsthemetabolismof
+chlorpromazine(Peetetal.,1980),lignocaine
+(Ochsetal.,1980)andtheophylline(Conrad&
+Nyman,1980;Minersetal.,1985)and,in
+common withsomeother,B-adrenoceptorantagonists,antipyrine(Baxetal.,1983;Green-
+blattetal.,1978;Parkeretal.,1984).Theinhibi-
+tionofoxidativemetabolismbypropranololis
+relatedtoitslipidsolubility(Baxetal.,1981;
+Deaconetal.,1983),itmaybeselectivefor
+differentformsofcytochromeP450andis
+possiblyconcentrationdependent(Minersetal.,
+1984).
+Inanimalstudiespropranololinlargedoses
+hasa protectiveeffectagainstparacetamol-
+inducedhepaticnecrosis(Baxetal.,1983;Legors,
+1976).However,inastudyofsixindividualsa
+relativelysmalldoseofpropranolol(80mgdaily
+for6days)didnotaffectthekineticsofpara-
+cetamol(Sanchez-Martinezetal.,1985).
+Theaimofthisstudywastore-investigatethe
+effectofpropranololonparacetamoldisposition
+inman.Inordertoconfirmtheeffectofpro-
+pranololon drugmetabolisingcapacitya
+measurementofantipyrinekineticswasin-
+corporatedinthestudydesign.
+Method
+Subjects
+Sixmalesandfourfemales,allclinicallyhealthy,
+agedbetween21and32yearsandweighingfrom
+51to85kg(median68kg)participatedinthe
+Correspondence:DrCliveJ.C.Roberts,DepartmentofMedicinc,BristolRoyalInfirmary,Bristol,BS28HW
+261
+262 0.Z.Barakaetal.
+studywhichwasapprovedbytheBristoland
+WestonHealthAuthorityEthicsCommittee.
+Allwerenon-smokers,usedalcoholinmodera-
+tionanddidnottakeotherdrugs,includingthe
+oralcontraceptive.
+Studydesign
+Thestudywasadouble-blind,crossoverinvesti-
+gationcomprisingtwoperiodsof5dayseach
+separatedby12days.Subjectsreceivedina
+randomordereitherracemicpropranololHCI
+80mgormatchedplacebotabletstwicedailyfor
+4days.Subjectsrefrainedfromtakingalcohol
+duringthestudyandreportedtotheclinical
+laboratoryat09.00hafteranovernightfaston
+days4and5ofeachtreatmentperiod.
+Onday4asingleoraldoseofparacetamol
+(1500mg)wasadministeredandthesubjects
+continuedtofastfor2h.Venousbloodsamples
+(5ml)werecollectedat0,0.5,1,1.5,2,3,4,5,
+6,8,12and24h.A completeurinecollection
+wasmadeforthefirst24h followingdrug
+administration.
+Onday5thesubjectsreceivedasingleoral
+doseof600mgantipyrine.Saliva(2ml)was
+obtainedat0,3,6,9,12and24h.Allplasma
+sampleswereseparatedimmediatelyandto-
+getherwithaliquotsoftheurineandsaliva
+samplestheywerefrozenandstoredat-20°C
+untilassayed.
+Antipyrinewasassayedinsalivabyh.p.l.c.
+(Danhofetal.,1979).Paracetamolanditsmeta-
+bolitesinplasmaandurinewereassayedbythe
+h.p.l.c.methodofAdriaenssens& Prescott
+(1978)modifiedbytheuseofmetacetamolas
+internalstandard.Themobilephasewas0.1M
+potassiumdihydrogenphosphate,98% v/v
+formicacidandpropan-2-ol(100:0.16:1.5vlv/v).
+Thismethodwasabletomeasureparacetamol
+anditsmetabolitesat0.1,ugml-'atasignalto
+noiseratioof2:1orbetter.Theinter-assayco-
+efficientsofvariationforparacetamolandallthe
+metaboliteswerenogreaterthan7% at2,ug
+ml-',4%at10ugml-'and3%at50,gml-'.The
+paracetamolmetabolitesusedasstandardswere
+donatedbySterlingWinthropLaboratories
+(Alnwick).Thestandardmetabolitesolutions
+werepreparedandstoredat-20°Cfor8weeks
+duringwhichtimerepeatedassayagainstfreshlypreparedsolutionsshowednoevidenceofin-
+stability.Allurinesampleswereassayedwithin
+6weeksofcollection.
+Pharmacokineticanalysis
+Theplasmaeliminationhalf-life(t,)ofpara-
+cetamolwascomputedbyleastsquareslinear
+regressionoftheterminalpartofthelogdrug
+concentration-timecurve.Theareaunderthe
+plasmadrugconcentration-timeprofile(AUC)
+wascalculatedasfollows:theareauptotheend
+ofsamplingwascalculatedusingthelinear
+trapezoidalruleandtheremainingareawas
+extrapolatedtoinfinityusingtheterminallog
+drugconcentration-timeslope.Thesystemic
+clearanceofparacetamolcouldnotbeassessed
+intheabsenceofameasurementofbioavail-
+ability.However,theoralclearance(CLP,)was
+estimatedfrom:
+CLp(= Dose/AUC
+Thepartialclearanceofparacetamoltoeachof
+itsmetabolites(CLm,)wascalculatedfrom
+CLm= Ae(m)
+AUC
+whereAe(m)= Amountofmetabolitere-
+coveredinurine.
+Statisticalanalysis
+Student'st-testforpaireddatawasusedto
+comparemeasurementsonpropranololwith
+thoseonplacebo.
+Results
+Allsubjectscompletedthestudywithoutadverse
+effects.Oneormoreurinecollectionshadbeen
+collectedincorrectlybythreesubjectsandtheir
+urinaryresultswereexcludedfromtheanalysis.
+Antipyrinekinetics
+Propranololincreasedtheeliminationhalf-life
+ofantipyrinefrom11.2±2.5h(mean±s.d.)to
+12.4±3.5h(P<0.05)anddecreaseditsclear-
+ancefrom58.1±19.3mlmin-'to51.5±18.3ml
+min-'(P<0.05)comparedwithplacebo.
+Paracetamolandmetabolitesinplasmaandurine
+The plasmaconcentrationofparacetamol
+reachedapeakof27.0± 10.8,ugml-'after
+propranololcomparedwith18.0±6.1ptgml-'followingplacebo(P< 0.01)(Figure1).Pro-
+pranololincreasedthehalf-lifeofparacetamol
+from2.7± 0.6to3.4± 0.3h(P< 0.05)and
+lowereditsoralclearancefrom364± 92
+mlmin-'to313±28mlmin-'(P<0.05).
+Propranololdecreasedthepartialclearanceof
+paracetamoltotheoxidisedmetabolites-the
+cysteineandmercapturate-by16± 3% and
+Shortreport
+TableI Partialmetabolicclearancesofparacetamolmetabolitesandpercentagerecovery
+ofadministereddoseinsevenhealthyvolunteers(mlmin-';mcan±s.d.)
+Gluc-ir-onideSull)hateCysteineMercapturate% Recovery
+Placebo 241.0±91.0 91.2± 19.69.2+2.4 12.7±3.7 77.9± 16.3
+Propranolol177.0±66.9*75.2±19.57.7+2.1* 8.0±)3.7*88.3±10.4
+*P<0.05comparedwithplacebo-Student'st-test
+59 t ,. j -'-s 3**'|| 0x |ts
+' .4.
+._ . . *4. ,i:~, .,,
+1#~~~~~~~1
+ )2,. g 3§z£-}}.# ,t-p|.;1 ->>'
+ V..
+Figure1 Plasmaparacetamolconcentrations
+followingoraladministrationof15(Xmgparacetamolto10healthysubjectsaftertreatmentwithplacebo(0)orpropranolol(0)for4days(mean±s.e.mean).
+32± 7% (P< 0.05),respectivelyandtothe
+glucuronideby27±7%(P< 0.05).However,
+thepartialclearanceofparacetamoltosulphate'was notchangedsignificantlybypropranololtreatment(Table1).
+Discussion
+Theresultsofthisstudysuggestthattheincrease
+intheplasmahalf-lifeandtheloweredclearance
+ofparacetamolcausedbypropranololare
+mainlyduetoinhibitionofglucuronidationand
+oxidativepathways.Thedoseofpropranololusedinthisstudywas
+showntobesufficienttoinhibithepaticdrug
+metabolisingenzymesbythesignificantlower-
+ingofantipyrineclearance,althoughthiswas
+lessthanthatreportedbyothers(Baxetal.,
+1981;Greenblattetal.,1978).
+Thedecreasedoralclearanceofparacetamol
+wasincontrasttothefindingsofSanchez-
+Martinezetal.(1985)whoreportedalackof
+effectofpropranololatadoseof80mgonce
+adayfor6daysonthekineticsofIgoral
+paracetamol.However,inthatstudynoin-
+dependentmeasurementofenzymeinhibition
+wasmade.Inthepresentstudywehaveused
+twicethedoseofpropranololandhaveprovided
+apositivecontrolforenzymeinhibitionbythe
+changesinantipyrineclearance.Thedoseused
+maybecriticalastheextentofenzymeinhibition
+bypropranololisdosedependent(Minersetal.,
+1985).
+Thedecreasedpartialclearancetothecysteine
+andmercapturatemetabolitessuggeststhat
+propranololsignificantlyinhibitstheoxidative
+pathwayofparacetamol.Althoughthemean
+decreaseinpartialclearancetothemercapturate
+wasgreaterthanthattothecysteinederivative
+thiswasnotsignificant.Thismechanismmay
+explaintheobservationthatpropranololhada
+protectiveeffectonparacetamol-inducedhepatic
+necrosisinmice(Baxetal.,1983;Legors,1976).
+Propranololsignificantlyimpairedtheglucuro-
+nidationofparacetamolbutsulphationwasnot
+affected.Thiscontrastswiththefindingof
+Brunketal.(1974)thatpropranololdidnot
+inhibitthemetabolismofmorphinewhich
+mainlyundergoesconjugationandwiththoseof
+Ochsetal.(1984)andHawksworthetal.(1984)
+whofoundadecreaseintheclearanceofdiazepam
+(whichundergoesoxidationtotheN-desmethyl
+product)butnoeffectofpropranololonthe
+kineticsoftwobenzodiazepineswhichare
+glucuronidated,namelylorazepamand
+alprazolam.Thesedifferencesmayreflectthe
+factthatglucuronidationiscarriedoutbyseveral
+isoenzymeswithvaryingsubstratespecificity
+(Dutton,1966).
+Therearetwopossibleimplicationsofour
+findings.Thus,propranololmayaffordsome
+protectionagainstparacetamol-inducedhepatic
+damageanditmay prolongtheeffectof
+paracetamol.
+We thankICIPharmaceuticalDivisionforsupplying
+thedrugs.
+263
+
+264 0.Z.Barakaetal.
+References
+Adriaenssens,P.1.& Prescott,L.F.(1978).High
+performanceliquidchromatographicestimationof
+paracetamolmetabolitesinplasma.Br.J.clin.
+Pliarmac..6.87-88.
+Bax,N.D.S.,Lennard.M.S.&Tucker,G.T.(1981).
+Inhibitionof antipyrinemetabolismby P-adrenoceptorantagonists.Br.J.clin.Pliarmac..
+12.779-784.
+Bax.N.D.S.,Lennard.M.S.,Al-Asady.S.,Deacon.
+C.S.,Tucker.G.T.&Woods,H.(1983).Inhibition
+ofdrugmetabolismbybetaadrenoceptorantago-
+nists.Drugs,25(Suppl.2).121-126.
+Brunk.S.F..Delle.M.& Wilson,W. R.(1974).
+Effectofpropranololonmorphinemetabolism.
+Clin.Pharmac.Thler..28.463-467.
+Conrad,K.A.& Nyman.D.W.(1980).Effectof
+metoprololandpropranololontheophyllineelimi-
+nation.Clin.Plharmac.Thler..33.133-138.
+Corcoran.G.B..Mitchell.J.R..Vasihnav.Y.N.&
+Horning.E.C.(1980).Evidencethatacetamino-
+phenand n-hydroxyacetaminophenforma
+commonarylatingintermediate.n-acetylp-benzo-
+quinoneimine.Mol.Plharmac..18.536-542.
+Danhof.M..deGrootvanderVis.E.& Breimer.D.D.(1979).Assayofantipyrineanditsprimary
+metabolitesinplasma.salivaandurinebyhigh
+performanceliquidchromatographyandsomepre-
+liminaryresultsinman.Phtarmacology,18.210-
+223.
+Deacon.C.S..Lennard.M.S.,Bax.N.D.S..Woods.
+H.S.& Tucker.G.T.(1981).Inhibitionofoxi-
+dativedrugmetabolismby ,B-adrenoceptor
+antagonistsisrelatedtotheirlipidsolubility.Br.J.
+clin.Plharmac.,12.429-430.
+Dutton.G.J.(1966).Thebiosynthesisofglucuronide.
+InGlucuronicacid.ed.Dutton.G.J.NewYork:
+AcademicPress.inc.
+Greenblatt,D.G..Frankie.K.& Huffman.D.H.
+(1978).Impairmentofantipyrineclearancein
+humanbypropranolol.Circulation.57.1161-1-164.
+Hawksworth.G..Betts.T.,Crowe.A..Nyemitei-
+Addo,L..Parry.K..Petrie.J.C..Raffle.A.&
+Parsons,A. (1984).Diazepam/n-adrenoceptorantagonistinteractions.Br.J.clin.Plharmac..17.
+69S-76S.
+Legors.J.(1976).Animalstudies.Atheoreticalbasis
+fortreatment.J.int.med.Res..4(Suppl.4).46-54.
+Meredith.T.J.&Goulding.R.(1980).Paracetamol.
+Postgrad.med.J.,56,459-473.
+Miners.J.O..Wing.L.M.H..LillywhiteK.J.&
+Smith.K.J.(1984).Failureoftherapeuticdoses
+of 3-adrenoceptorantagoniststoalterthedis-
+positionoftolbutamideandlignocaine.Br.J.clin.
+Pliarmac..18,853-860.
+Miners,J.O.,Wing,L.M.H..Lillywhite,K.J.&
+Robson,R.A.(1985).Selectivityanddosedepen-
+dencyoftheinhibitoryeffectofpropranololon
+theophyllinemetabolisminman.Br.J.clin.
+Plharmac..20,219-223.
+Mitchell,M.C.,Hanew,T.,Meredith,C.G.&
+Schenker,S.(1983).Effectoforalcontraceptive
+steroidonacetaminophenmetabolismandelimi-
+nation.Clin.Plharmac.Tlier..34.48-53.
+Mitchell,M.C..Schenker,S.&Speeg,K.V.(1984).
+Selectiveinhibitionofacetaminophenoxidation
+andtoxicitybycimetidineandotherhistamineH2-
+receptorantagonistsinvivoandinvitrointherat
+andinman.J.clin.Invest..73,383-391.
+Ochs,H.R.,Carstens.G.&Greenblatt.D.J.(1980).
+Reductioninlignocaineclearanceduringcon-
+tinuousinfusionandco-administrationofpro-
+pranolol.NewEngl.J.Med..303,373-377.
+Ochs,H.R.,Greenblatt,D.J.& Verburg-Ochs,B.
+(1984).Propranololinteractionswithdiazepam,
+lorazepamandalprazolam.Clin.Plharmac.Tiher..36.451-455.
+Parker,G.,Daneshmend,T.K.,Ene,M. D.&
+Roberts,C.J.C.(1984).Dobetablockersdiffer
+intheireffectsonhepaticmicrosomalenzymesand
+liverbloodflow?J.clin.Pliarmac..24,395-400.
+Peet,M.,Middlemass,D.M.&Yates.R.A.(1980).
+Pharmacokineticinteractionbetweenpropranolol
+andchlorpromazineinschizophrenicpatients.
+Lancet.ii,978.
+Perucca,E.& Richens,A.(1979).Paracetamolin
+normalsubjectsandinpatientstreatedwithanti-
+epilepticdrugs.Br.J.clin.Plharmac..7.201-206.
+Prescott,L.F.,Critchley,J.A.J.H.,Balali-Mood,
+M.& Pentland,B.(1981).Effectofmicrosomal
+enzymeinductiononparacetamolmetabolismin
+man.Br.J.clin.Plharmac..12,149-153.
+Sanchez-Martinez,V..Tucker,G.T.,Jackson,P.R.,
+Lennard,M.S..Bax,N.D.S.& Woods,H.F.
+(1985).Lackofeffectofpropranololonthekinetics
+ofparacetamolinman.Br.J.clin.Plharmac..20,
+548P.
+(Received14January1989,
+accepted16October1989)

papers/PKDB00047.md

@@ -0,0 +1,16 @@
+# Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man.
+
+A Lelo, D J Birkett, R A Robson, J O Miners
+
+*British journal of clinical pharmacology* (1986)
+
+PMID: 3756065
+DOI: 10.1111/j.1365-2125.1986.tb05246.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+The pharmacokinetics of caffeine (CA), paraxanthine (PX), theobromine (TB) and theophylline (TP) were studied in six healthy male volunteers after oral administration of each compound on separate occasions. The total plasma clearances of CA and PX were similar in value (2.07 and 2.20 ml min-1 kg-1, respectively) as were those for TP and TB (0.93 and 1.20 ml min-1 kg-1, respectively). The unbound plasma clearances of CA and PX were also similar in magnitude (3.11 and 4.14 ml min-1 kg-1, respectively) as were those of TP and TB (1.61 and 1.39 ml min-1 kg-1, respectively). The half-lives of TP and TB (6.2 and 7.2 h, respectively) were significantly longer than those of CA and PX (4.1 and 3.1 h, respectively). The volume of distribution at steady state of TP (0.44 l kg-1) was lower than that of the other methylxanthines (0.63-0.72 l kg-1). The unbound volume of distribution of TP (0.77 l kg-1) was however the same as that of TB (0.79 l kg-1) whereas the unbound volume of distribution of PX (1.18 l kg-1) was similar to that of CA (1.06 l kg-1).

papers/PKDB00047.pdf

@@ -0,0 +1,3 @@
+version https://git-lfs.github.com/spec/v1
+oid sha256:d25327ec16767c61c0b2ff3d1950e5c8ba42380d23f2fd4d33817c95a7b2ee11
+size 949649

papers/PKDB00047.txt

@@ -0,0 +1,544 @@
+Br.J.clin.Pharmac.(1986),22,177-182
+Comparativepharmacokineticsofcaffeineanditsprimary
+demethylatedmetabolitesparaxanthine,theobromineand
+theophyllineinman
+A.LELO,D.J.BIRKETT,R.A.ROBSON&J.0.MINERS
+DepartmentofClinicalPharmacology,FlindersMedicalCentre,BedfordPark,Adelaide,SouthAustralia
+1 Thepharmacokineticsofcaffeine(CA),paraxanthine(PX),theobromine(TB)and
+theophylline(TP)werestudiedinsixhealthymalevolunteersafteroraladministrationof
+eachcompoundonseparateoccasions.
+2 ThetotalplasmaclearancesofCAandPXweresimilarinvalue(2.07and2.20mlmin-
+kg-',respectively)aswerethoseforTPandTB(0.93and1.20mlmin-'kg-',respectively).
+TheunboundplasmaclearancesofCAandPXwerealsosimilarinmagnitude(3.11and
+4.14mlmin-'kg-',respectively)aswerethoseofTPandTB(1.61and1.39mlmin-tkg-',
+respectively).
+3 Thehalf-livesofTPandTB(6.2and7.2h,respectively)weresignificantlylongerthan
+thoseofCA andPX(4.1and3.1h,respectively).
+4 ThevolumeofdistributionatsteadystateofTP(0.441kg-')waslowerthanthatofthe
+othermethylxanthines(0.63-0.721kg-1).TheunboundvolumeofdistributionofTP(0.77
+1kg-)washoweverthesameasthatofTB(0.791kg-')whereastheunboundvolumeof
+distributionofPX(1.181kg-1)wassimilartothatofCA(1.061kg-').
+Keywordsmethylxanthinescaffeineparaxanthinetheobrominetheophylline
+drugmetabolism
+Introduction
+Thestructurally-relatednaturallyoccurringalka-
+loidscaffeine(1,3,7-trimethylxanthine;CA),
+theobromine(3,7-dimethylxanthine;TB)and
+theophylline(1,3-dimethylxaAthine:TP)(Figure
+1)areamongthemostwidelyandfrequently
+consumedcompoundsthroughouttheworld.It
+hasbeenestimated(Barone& Roberts,1984)
+thatthemeandailyintakeofCA intheUSA
+frombeveragessuchascoffee,teaandcolais3
+mgkg-'foralladultsinthegeneralpopulation.
+Inaddition,ithasbeenestimatedthatabout
+1,000prescriptiondrugproductsandabout
+2,000non-prescriptiondrugproductscontain
+CA (Barone& Roberts,1984).TBisamajor
+constituentofcocoaandaminorconstituentof
+teaandcoffee;ithasalsobeenincludedin
+certainpharmaceuticalpreparations.TPhasfound
+widespreadclinicaluseasabronchodilatorand
+alsooccursasaminorconstituentoftea.Along
+withtheisomericdimethylxanthineparaxanthine
+(1,7-dimethylxanthine;PX)(Figure1),which
+doesnotoccurnaturally,TPandTBareprimary
+metabolicproductsofCA.Arnaud& Welsch
+(1980)haverecentlydemonstratedthatPXis
+quantitativelythemostimportantdemethylation
+productofCA inhumans,withPXformation
+accountingforapproximately70%ofCAmeta-
+bolism.Indeed,inarecentstudy(Leloetal.,
+Correspondence:DrJ.0.Miners,DepartmentofClinicalPharmacology,FlindersMedicalCentre,Bedford
+Park,SouthAustralia5042
+177
+178 A.Leloetal.
+CH3H
+ OHCH -Ni6
+A3 94N N
+CH3
+CaffTeine
+o HN
+N." N
+CH3
+Theophylline
+CH0 1 3NHN
+N N
+CH3
+Theobromine
+CH0 1 3NCH3-N
+<N N
+H
+Paraxanthine
+Figure1 Structuresofcaffeineanditsdimethylxanthinemetabolites.
+1986)innormalteaandcoffeedrinkersinvesti-
+gatingtherelationshipofdailyCA intaketo
+plasmaconcentrationsofCA anditsdimethyl-
+xanthinemetabolites,weshowedthattheaverage
+24hplasmaconcentrationofPXwas2mg[-1,
+whereasthoseofTPandTBwere0.2mg[-and
+0.7mg1-1respectively.Thus,theindirectexpo-
+sureofnormalCA-consumerstoPXmaybe
+considerable.
+ConsistentwiththeclinicalimportanceofTP
+andthewidespreaduseofCA,theliterature
+relatingtothepharmacokineticsoftheseagents
+isextensive(forreviewssee:Bonati&Garattini,
+1984;Ogilvie,1978).However,thereisnoin-
+formationrelatingtothepharmacokineticsofPX
+inmanalthoughsomestudiesofTBpharmaco-
+kineticsandmetabolisminhumanshavebeen
+reported(Birkettetal.,1985;Drouillardetal.,
+1978;Minersetal.,1982,1985;Shivelyetal.,
+1985;Simonsetal.,1984;Tarkaetal.,1983).
+Therehasnotbeenanydirectcomparisonofthe
+pharmacokineticsofallmembersofthemethyl-
+xanthinegroupinhumans.Theaimofthepre-
+entstudywastodefineCA,TB,TPandPX
+pharmacokineticparametersinthesameindi-
+viduals,therebyprovidingthefirstkineticdata
+forPXinmanandenablingadirectcomparison
+ofthekineticsoftheseagentstobemade.
+Methods
+Subjects
+Subjectsweresixnon-smokingmalevolunteers,
+aged19-21years,weight62-104kg.Nosubject
+wasreceivinganymedicationsatthetimeofthe
+study,althoughallweremodestsocialdrinkers
+ofalcohol.Thesubjectswerehealthyasdeter-
+minedbymedicalhistory,physicalexamination
+andbiochemicalandhaematologicalmeasure-
+ments.Writteninformedconsentwasobtained
+fromeachsubjectandthestudieswereapproved
+bytheClinicalInvestigationandDrugand
+TherapeuticsAdvisoryCommitteesofFlinders
+MedicalCentre.
+Preparations
+CAandTB(bothB.P.)weresuppliedbyHamilton
+Laboratories(Adelaide,S.A.)andadministered
+ingelatincapsules.TPwasadministeredinthe
+formofNuelintablets(125mg,Riker).PXwas
+purchasedfromtheSigmaChemicalCo.(St
+Louis,MO,USA)andadministeredingelatin
+capsules.ThePXusedwasshowntobe> 99.8%
+purebyelementalanalysisandchromatography.
+PermissionwasobtainedfromtheAustralian
+Pharmacokineticsofcaffeineanditsdemethylatedmetabolites
+DepartmentofHealthfortheuseofPXinthis
+studysinceitisnotanapprovedsubstancefor
+useinhumans.
+Protocol
+EquimolaroraldosesofTP,TB,PX(250mgof
+each)andCA(270mg)wereseparatelyadmini-
+steredtoeachsubject.Subjectsfastedfromthe
+eveningpriortoanduntil4hfollowingmethyl-
+xanthineadministrationoneachstudyday.The
+methylxanthinedosewasadministeredwith
+150mlwateratapproximately08.00hofthe
+studyday.Thesubjectsabstainedfromallmethyl-
+xanthine-containingfoodsandbeveragesfor
+4dayspriortoandduringthebloodcollection
+periodfollowingeachmethylxanthineadmini-
+stration.Theorderofthemethylxanthinedoses
+wasrandomisedandatleast1weekseparated
+eachadministration.
+Oneachstudydayvenousbloodsamples(5ml
+intoanheparinisedtube)werecollectedthrough
+anindwellingcannulainsertedinaforearmvein
+priortoandat0.25,0.5,0.75,1,1.5,2,3,4,6,8
+and10hafterthemethylxanthinedose.The
+cannulawaskeptpatentwith0.9%w/vsodium
+chloridesolutioncontainingheparin5uml-'.Additionalsampleswerecollectedat24,28and
+32hpost-dosebyvenepuncture.Plasmawas
+separatedbycentrifugation(3,000gfor5min)
+andstoredat-20°Cuntilanalysed.
+Analyticalprocedures
+PlasmaconcentrationsofCA,TB,TPandPX
+weremeasuredbyahighperformanceliquid
+chromatographicmethod(Leloetal.,1986).
+Thismethodallowstheseparationofeachmethyl-
+xanthineinthepresenceoftheothersandhasa
+limitofsensitivityof0.1mg1-1foreachcom-
+pound.TheplasmaproteinbindingofCA,TB,
+TPandPXwasdeterminedintheblank(pre-
+dose)plasmasamplefromeachsubjectand
+wasmeasuredbyequilibriumdialysisusinga
+spectrapor-2cellulosemembrane(Spectrum
+MedicalIndustries).Plasma(1ml)wasintro-
+ducedintoonesideofthecell(Dianorm)and
+dialysedat37°Cfor3hagainstanequalvolume
+ofisotonicphosphatebuffer(pH7.4)containing
+eitherCA,TB,TPorPX.Thebindingofeach
+methylxanthinewasdeterminedforaddedcon-
+centrationsof2,4,6and8mgl-l.
+Analysisofresults
+Thefollowingparameterswereestimatedfor
+eachmethylxanthinefromtheplasmaconcentra-
+tiondata.Areaundertheplasmaconcentration-
+timecurve(AUC)wasmeasuredbythetrape-
+zoidalrulewithextrapolationtoinfinitetime.
+Eliminationhalf-life(t½Z)wascalculatedfrom
+theslopeoftheterminralportionofthecon-
+centration-timecurvebylinearleastsquares
+regressionandvolumeofdistributionatsteady
+state(V,,)bythemodel-independentprocedure
+ofBenet&Galeazzi(1979).Totalplasmaclear-
+ancewasdeterminedas:
+CL= Dose/(AUCxB.W.)
+whereB.W.isthebodyweightinkg.Unbound
+clearancewascalculatedas:
+CLu= CL/fu
+wherefuisthefractionofunbounddrugin
+plasma.
+Allresultsareexpressedasmean+ s.d.The
+meanvaluesofeachpharmacokineticparameter
+forthemethylxanthineswerecomparedby
+analysisofvariance.Individualcomparisonswere
+performedusingtheNeuman-KeulsStudentised
+rangetest.Correlationsbetweenunboundclear-
+ancesweredeterminedbylinearregression.The
+factorsrequiredfortheconversionofplasma
+concentrationsofthedimethylxanthines(TP,
+TB,PX)andCAfrommg1[1toS.I.units(,umol
+1-1)are5.55and5.15,respectively.
+Results
+Meanpharmacokineticparametersforeachof
+themethylxanthinesaresummarisedinFigure2.
+Representativeplasmaconcentration-timepro-
+filesareshowninFigure3.
+ThetotalplasmaclearancesofCA andPX
+weresimilarinmagnitude(2.07+0.96and2.20
++ 0.91mlmin-'kg-l,respectively)aswere
+thoseforTPandTB(0.93+ 0.22and1.20±
+0.40mlmin-'kg-',respectively).Althoughthe
+totalplasmaclearancesofCA andPX were
+significantlygreater(P<0.025)thanthatofTP,
+thedifferencesbetweenthetotalclearanceof
+TBandthoseofCAandPXwerenotstatistically
+significant.Therewasconsiderableinterindivi-
+dualvariabilityinthetotalclearancesofCA(3.2
+fold),PX(2.7fold)andTB(2.6fold)butTP
+clearancewaslessvariable(1.6foldrange).The
+half-livesofCA andPXweresimilarinvalue
+(4.1+ 1.3and3.1+ 0.8h,respectively)and
+significantlyshorter(P<0.01)thanthoseofTP
+andTB(6.2+ 1.4and7.2+ 1.6h,respectively).
+ThemeanfreefractionsofCA,PX,TPandTB
+were0.68+0.04,0.54+0.04,0.58+ 0.06and
+0.86± 0.03,respectively.Proteinbindingof
+eachofthemethylxanthineswasconcentration
+independentovertherangestudied.Aswith
+179
+I C.)
+0
+I-to
+0 E _ _
+cLE_i_
+5
+4
+3
+2
+1
+0
+6i
+CD 5C
+m
+ Cu-
+°-T 4 10) u
+1 0 E 2
+0
+.0
+c 1
+0
+1.6
+0)
+ __~~~~~~~~~~~~1
+C
+0
+.0 _~~~~~~~~~~~~~~~~~(A
+la
+0.
+ _ .~~~~0
+0
+| 11I b~~
+0.0
+4- -
+0 -
+0 cm
+E--w
+M =-
+'5r-> 0-0,'rC nD .00 ,r-
+.0V;C 1.D
+1.21-
+0.8F
+0.4F
+0.0L.
+Figure2 Mean±s.d.pharmacokineticparametersofcaffeine(B),paraxanthine(EI),theobromine(0)and
+theophylline(H)insixhealthyvolunteersreceivingeachcompound(250-270mgp.o.)onfourseparateoccasions.
+totalclearance,theunboundplasmaclearances
+ofCAandPXweresimilar(3.11±1.50and4.14
+± 1.85mlmin-'kg-1,respectively)aswere
+thoseofTPandTB(1.61±0.41and1.39_0.44
+mlmin-'kg-1,respectively).Therewasalsoa
+similartrendinthedegreeofvariabilityinun-
+boundclearancewiththatpreviouslyobserved
+fortotalclearance,thevariabilityinTPtotal
+ 18 16 24 32
+-If
+:1 K-7
+d 0.0 a
+- I
+0 8 16 24 32
+Time(h)
+Figure3 Plasmaconcentration-timecurvesofcaffeine(0),paraxanthine(0),theobromine(0)and
+theophylline(O),(a)afteroraladministrationofeachcompound(250-270mg)onseparateoccasionstoasingle
+subject,and(b)afteroraladministrationofcaffeine(270mg)tothesame subject.
+180 A.Leloetal.
+8k
+61-
+-c
+.C
+0
+._._
+UJ
+41
+ii2
+oI
+100r
+1-0
+C
+0; 600
+c 40
+0.0C
+=) 201
+I-
+L
+_
+a
+E
+C0-W
+C
+C
+C._
+Co0
+EC,Cu
+0*1L'L
+0
+'o0r 6r
+1'6rt
+QnL_
+--I
+oI
+1
+
+Pharmacokineticsofcaffeineanditsdemethylatedmetabolites
+clearance(1.7foldrange)beinglessthanthatfor
+TB(2.5fold),PX(2.6fold)andCA(3.6fold).
+ThedifferencesinTPandTBproteinbinding
+reversedtheorderofTP andTB unbound
+clearancecomparedtothatobservedfortotal
+clearance.Whiletheunboundplasmaclearance
+ofPXwassignificantlygreater(P<0.025)than
+thoseofTPandTB,thedifferencesbetweenthe
+unboundclearancesofCAandeachoftheother
+methylxanthineswerenotsignificant.The
+volumeofdistributionatsteadystateforTP
+(0.44± 0.081kg-)waslower(P< 0.05)than
+thoseoftheothermethylxanthines(0.63-0.711
+kg-).TheunboundvolumeofdistributionofTP
+(0.77±0.171kg-)washoweversimilartothat
+ofTB(0.79±0.151kg-'),whereastheunbound
+volumeofdistributionofPX(1.18+0.371kg-')wassimilartothatofCA(1.06±0.261kg-)and
+itwassignificantlygreater(P<0.05)thanthose
+ofTPandTB.
+TheunboundplasmaclearanceofCA was
+significantlycorrelated(P<0.05)withthoseof
+TP(r=0.91),TB(r=0.87)andPX(r=0.90).
+Inaddition,therewasasignificant(P< 0.05)
+correlationbetweentheunboundplasmaclear-
+ancesofTPandTB(r=0.91)butthesewerenot
+significantlycorrelatedwiththeunboundclear-
+anceofPX(r= 0.75and0.71respectively).
+Discussion
+ThisisthefirstformalstudyofPXpharmaco-
+kineticsinmanandthefirstdirectcomparisonof
+thepharmacokineticsofCA,PX,TPandTB.
+Interestingly,PX totalplasmaclearanceand
+unboundplasmaclearanceweretwotothree-
+foldgreaterthanthevaluesfortheisomeric
+dimethylxanthinesTPandTB.PX totaland
+unboundplasmaclearanceswere,however,
+similartothoseofthetrimethylxanthineCA.PX
+andCAplasmahalf-liveswerecorrespondingly
+shorterthanthoseforTPandTB.A similar
+trendwasobservedinarecentstudyofPX
+pharmacokineticsintherat(Bortolottietal.,
+1985).Forequivalentintravenousdosesofthe
+methylxanthinesadministeredtorats,theplasma
+clearancesandhalf-livesofPX andCA were
+similarwhereastheplasmaclearancesofTPand
+TBwereapproximatelyhalfthatforPXandthe
+half-livesofTP andTB wereapproximately
+doublethatofPX.Thepharmacokineticpara-
+metersofCA,TPandTBdeterminedinthis
+studyaresimilartothosegenerallyreportedin
+theliterature(Birkettetal.,1982,1985;Blanchard
+& Sawers,1983a;Bonatietal.,1982;Minerset
+al.1982,1985;Ogilvie,1978;Renneretal.,
+1984;Tarkaetal.,1983).
+FollowingCA administrationtheorderof
+dimethylxanthineplasmaconcentrationswas
+PX>TB>TP(Figure3b).Thisisconsistent
+withpreviousstudies(Leloetal.,1986;Tang-
+Liuetal.,1983)whichhavemeasuredplasma
+concentrationsofCA-deriveddimethylxanthines.
+Tang-Liuetal.(1983)havereportedthatthelog
+plasmaconcentration-timeplotsforeachofthe
+dimethylxanthinesformedfromCA arenon-
+linearandtherewasasuggestionofthesame
+effectinthepresentstudy.Thenon-linearmeta-
+boliteconcentration-timeplotspresumablyarise
+fromsimultaneousformation(fromCA)and
+eliminationofeachdimethylxanthineandareto
+beexpectedwhentheeliminationrateconstants
+forthemetaboliteandparentdrugaresimilarin
+magnitude(Houston,1982).
+InthisreportithasbeenassumedthatPX
+absorptionfromthegastrointestinaltractis
+complete.Previousstudies(Blanchard&Sawers,
+1983b;Minersetal.,1982;Ogilvie,1978)have
+demonstratedthatCA,TBandTPareessentially
+completelyabsorbedandPXwouldnotbeex-
+pectedtobedifferentinthisrespect.InaPX
+metabolismstudyinhumansArnaud&Welsch
+(1980)demonstratedthatapproximately60%of
+orallyadministeredPXmayberecoveredinthe
+urineasunchangeddrugandknownxanthine
+anduratemetabolites.Callahanetal.(1982,
+1983)havefurthershownthattheformation
+ofpolarring-openeduracilmetabolitesofPX
+accountsforupto40%ofPXmetabolismin
+man.Availablemetabolicdatathereforesuggests
+thatPX,liketheothermethylxanthines,iscom-
+pletelyabsorbedafteroraldoses.
+Inthepresentstudytherewerepositivecorre-
+lationsbetweentheunboundclearancesforall
+themethylxanthinesbutthoseforPX/TPand
+PXFJBdidnotquitereachstatisticalsignificance.
+Thisisconsistentwithourprevioussuggestion
+thatacommongroupofcytochromeP450iso-
+zymesundersimilarregulatorycontrolisinvolved
+inthemetabolismofthemethylxanthines(Birkett
+etal.,1985).Atleasttwoformsofcytochrome
+P450appeartobeinvolvedinTPandTBmeta-
+bolism(Birkettetal.,1982,1985;Minersetal.,
+1985),althoughtherelationshipoftheseisozymes
+tothoseinvolvedinCAandPXmetabolismis
+lessclear.WhereasN-demethylationsandC(8)-
+oxidationaretheprimarymetabolicpathwaysof
+CA,TBandTPmetabolism,amajorpathway
+forPXmetabolisminvolvestheformationofa
+ring-openeduracilderivative.Thelowercorre-
+lationcoefficientsforthecomparisonsbetween
+theunboundclearancesofPX andtheother
+dimethylxanthines(TBandTP)maybedueto
+theinvolvementofadifferentenzyme(s)inuracil
+formation.
+181
+182 A.Leloetal.
+References
+Amaud,M.J.& Welsch,C.(1980).Caffeinemeta-
+bolisminhumansubjects.NinthInternational
+ColloquiumonScienceandTechnologyofCoffee,
+London,pp.385-395.AssociationScientifique
+InternationaleduCafe.
+Barone,J.J.&Roberts,H.(1984).Humanconsump-
+tionofcaffeine.InCaffeine:Perspectivesfrom
+recentresearch,ed.Dews,P.B.,pp.59-73.Berlin:
+Springer-Verlag.
+Benet,L.Z.&Galeazzi,R.L.(1979).Noncompart-
+mentaldeterminationofsteadystatevolumeof
+distribution.J.pharm.Sci.,68,1071-1074.
+Birkett,D.J.,Grygiel,J.J.&Miners,J.0.(1982).
+Metabolicdispositionofthemethylxanthinesin
+man.InMethodsinclinicalpharmacology,no.3:
+Theophyllineandothermethylxanthines,eds.
+Rietbrock,N.,Woodcock,B.G.&Staib,A.H.,
+pp.149-158.Braunschweig/Wiesbaden:Friedr.
+Vieweg&Sohn.
+Birkett,D.J.,Dahlqvist,R.,Miners,J.O.,Lelo,A.
+&Billing,B.(1985).Comparisonoftheophylline
+andtheobrominemetabolisminman.DrugMetab.
+Disp.,13,725-728.
+Blanchard,J.&Sawers,S.J.A.(1983a).Comparative
+pharmacokineticsofcaffeineinyoungandelderly
+men.J.Pharmacokin.Biopharm.,11,109-126.
+Blanchard,J.&Sawers,S.J.A.(1983b).Theabsolute
+bioavailabilityofcaffeineinman.Eur.J.clin.
+Pharmac.,24,93-98.
+Bonati,M.,Latini,R.,Galletti,F.,Young,J.F.,
+Tognoni,G.&Garattini,S.(1982).Caffeinedis-
+positionafteroraldoses.Clin.Pharmac.Ther.,32,
+98-106.
+Bonati,M.& Garattini,S.(1984).Interspeciescom-
+parisonofcaffeinedisposition.InCaffeine:Per-
+spectivesfromrecentresearch,ed.Dews,P.B.,
+pp.48-56.Berlin:Springer-Verlag.
+Bortolotti,A.,Jiritano,L.& Bonati,M.(1985).
+Pharmacokineticsofparaxanthine,oneofthe
+primarymetabolitesofcaffeine,intherat.Drug
+Metab.Disp.,13,227-231.
+Callahan,M.M.,Robertson,R.S.,Arnaud,M.J.,
+Branfman,A.R.,McComish,M.F.& Yesair,
+D.W.(1982).Humanmetabolismof[1-methyl-14C]-and[2-14C]caffeineafteroraladministration.
+DrugMetab.Disp.,10,417-423.
+Callahan,M.M.,Robertson,R.S.,Branfman,A.R.,
+McComish,M.F.&Yesair,D.W.(1983).Com-
+parisonofcaffeinemetabolisminthreenon-smoking
+populationsafteroraladministrationofradiolabeled
+caffeine.DrugMetab.Disp.,11,211-217.
+Drouillard,D.D.,Vessell,E.S.&Dvorchik,B.H.
+(1978).Studiesontheobrominedispositionin
+normalsubjects.Clin.Pharmac.Ther.,23,
+296-302.
+Houston,J.B.(1982).Drugmetabolitekinetics.
+Pharmac.Ther.,15,521-552.
+Lelo,A.,Miners,J.0.& Birkett,D.J.(1986).
+Assessingcaffeineexposure:caffeinecontentof
+beverages,caffeineintakeandplasmaconcentra-
+tionsofmethylxanthines.Clin.Pharmac.Ther.,
+39,54-59.
+Miners,J.O.,Attwood,J.& Birkett,D.J.(1982).
+Theobrominemetabolisminman.DrugMetab.
+Disp.,10,672-675.
+Miners,J.O.,Attwood,J.,Wing,L.M.H.&Birkett,
+D.J.(1985).Influenceofcimetidine,sulfinpyrazone
+andcigarettesmokingontheobrominemetabolism
+inman.DrugMetab.Disp.,13,598-601.
+Ogilvie,R.I.(1978).Clinicalpharmacokineticsof
+theophylline.Clin.Pharmacokin.,3,267-293.
+Renner,R.,Wietholtz,H.,Huguenin,P.,Arnaud,
+M.J.& Preisig,R.(1984).Caffeine:amodel
+compoundformeasuringliverfunction.Hepatology,
+4,38-46.
+Shively,C.A.,Tarka,S.M.,Arnaud,M.J.,Dvorchik,
+B.H.,Passananti,G.T.&Vessell,E.S.(1985).
+Highlevelsofmethylxanthinesinchocolatedonot
+altertheobrominedisposition.Clin.Pharmac.
+Ther.,37,415-424.
+Simons,F.E.R.,Simons,K.J.& Becker,A.B.
+(1984).Thebronchodilatoreffectsandpharmaco-
+kineticsofcaffeine,theobromineandtheophylline
+inasthma.InSustainedreleasetheophyllineinthe
+treatmentofchronicreversibleairwaysobstruction,
+eds.Jonkman,J.H.G.,Jenne,J.W.&Simons,
+F.E.R.,pp1-8.Amsterdam:ExcerptaMedica.
+Tang-Liu,D.D.,Williams,R.L.& Riegelman,S.
+(1983).Dispositionofcaffeineanditsmetabolites
+inman.J.Pharmac.exp.Ther.,224,180-185.
+Tarka,S.M.,Arnaud,M.J.,Dvorchik,B.H.&
+Vessell,E.S.(1983).Theobrominekineticsand
+metabolicdisposition.Clin.Pharmac.Ther.,34,
+546-555.
+(Received6November1985,
+accepted12April1986)

papers/PKDB00063.md

@@ -0,0 +1,26 @@
+# Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A.
+
+Sandrine Turpault, William Brian, Robert Van Horn, Alix Santoni, Franck Poitiers, Yves Donazzolo, Xavier Boulenc
+
+*British journal of clinical pharmacology* (2009)
+
+PMID: 20002088
+DOI: 10.1111/j.1365-2125.2009.03548.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+**WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:** * Numerous cocktails using concurrent administration of several cytochrome P450 (CYP) isoform-selective probe drugs have been reported to investigate drug-drug interactions in vivo. * This approach has several advantages: characterize the inhibitory or induction potential of compounds in development toward the CYP enzymes identified in vitro in an in vivo situation, assess several enzymes in the same trial, and have complete in vivo information about potential CYP-based drug interactions.
+
+**WHAT THIS STUDY ADDS:** * This study describes a new cocktail containing five probe drugs that has never been published. * This cocktail can be used to test the effects of a new chemical entity on multiple CYP isoforms in a single clinical study: CYP1A2 (caffeine), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A (midazolam) and was designed to overcome potential liabilities of other reported cocktails.
+
+**AIMS:** To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone.
+
+**METHODS:** This was an open-label, single-dose, randomized, six-treatment six-period six-sequence William's design study with a wash-out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg(-1) midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log-transformed C(max), AUC(last) and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte C(max), AUC(last) and AUC.
+
+**RESULTS:** There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25.
+
+**CONCLUSION:** The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug-drug interactions in vivo.

papers/PKDB00063.pdf

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papers/PKDB00063.txt

@@ -0,0 +1,707 @@
+Pharmacokinetic assessment
+of a five-probe cocktail for
+CYPs 1A2, 2C9, 2C19, 2D6
+and 3A
+Sandrine Turpault, William Brian, Robert Van Horn, Alix Santoni, 2
+Franck Poitiers, 3 Yves Donazzolo4 & Xavier Boulenc 1
+Global Metabolism and Pharmacokinetics, Sanofi-Aventis, Malvern, PA, USA,1GMPK and 2Clinical and
+Exploratory Pharmacology, Sanofi-Aventis, Montpellier,3Biostatistics, Sanofi-Aventis, Chilly-Mazarin
+and 4Optimed, Gieres, France
+Correspondence
+Dr Sandrine Turpault, Global Metabolism
+and Pharmacokinetics, Sanofi-aventis, 9
+Great Valley Parkway, Malvern, PA, USA.
+Tel: +1 610 889 6592
+Fax: +1 610 889 6923
+E-mail:
+sandrine.turpault@sanofi-aventis.com
+----------------------------------------------------------------------
+Keywords
+cocktail, CYP ,in vivo drug–drug
+interaction
+----------------------------------------------------------------------
+Received
+15 December 2008
+Accepted
+17 August 2009
+WHAT IS ALREADY KNOWN ABOUT
+THIS SUBJECT
+• Numerous cocktails using concurrent
+administration of several cytochrome P450
+(CYP) isoform-selective probe drugs have
+been reported to investigate drug–drug
+interactions in vivo.
+• This approach has several advantages:
+characterize the inhibitory or induction
+potential of compounds in development
+toward the CYP enzymes identified in vitro
+in an in vivo situation, assess several
+enzymes in the same trial, and have
+complete in vivo information about
+potential CYP-based drug interactions.
+WHAT THIS STUDY ADDS
+• This study describes a new cocktail
+containing five probe drugs that has never
+been published.
+• This cocktail can be used to test the effects
+of a new chemical entity on multiple CYP
+isoforms in a single clinical study: CYP1A2
+(caffeine), CYP2C9 (warfarin), CYP2C19
+(omeprazole), CYP2D6 (metoprolol), and
+CYP3A (midazolam) and was designed to
+overcome potential liabilities of other
+reported cocktails.
+AIMS
+To assess the pharmacokinetics (PK) of selective substrates of CYP1A2
+(caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), CYP2D6
+(metoprolol) and CYP3A (midazolam) when administered orally and
+concurrently as a cocktail relative to the drugs administered alone.
+METHODS
+This was an open-label, single-dose, randomized, six-treatment
+six-period six-sequence William’s design study with a wash-out of 7 or
+14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg
+metoprolol, 0.03 mg kg
+-1 midazolam, 20 mg omeprazole and 10 mg
+warfarin individually and in combination (cocktail). Poor metabolizers
+of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were
+obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for
+midazolam, 312 h for warfarin and the cocktail. Three different
+validated liquid chromatography tandem mass spectrometry methods
+were used. Noncompartmental PK parameters were calculated.
+Log-transformed C
+max,A U Clast and AUC for each analyte were analysed
+with a linear mixed effects model with fixed term for treatment,
+sequence and period, and random term for subject within sequence.
+Point estimates (90% CI) for treatment ratios (individual/cocktail) were
+computed for each analyte C
+max,A U Clast and AUC.
+RESUL TS
+There was no PK interaction between the probe drugs when
+administered in combination as a cocktail, relative to the probes
+administered alone, as the 90% CI of the PK parameters was within the
+prespecified bioequivalence limits of 0.80, 1.25.
+CONCLUSION
+The lack of interaction between probes indicates that this cocktail
+could be used to evaluate the potential for multiple drug–drug
+interactions in vivo.
+British Journal of Clinical
+Pharmacology
+DOI:10.1111/j.1365-2125.2009.03548.x
+928 / Br J Clin Pharmacol / 68:6 / 928–935 © 2009 The Authors
+Journal compilation © 2009 The British Pharmacological Society
+Introduction
+Multiple drug therapy is common in clinical practice. The
+resultant potential for drug–drug interactions (DDIs) is a
+safety concern. Therefore, there is a need to identify pos-
+sible DDIs during early drug development. This typically
+begins with in vitro evaluation of a new chemical entity as
+an inhibitor or inducer of CYP isoforms. Positive in vitro
+findings then lead to follow-up studies in vivo . However,
+conducting multiple clinical drug interaction trials is costly
+and time-consuming. With a drug cocktail, more than one
+interaction can be tested in a single crossover study, as it
+involves the simultaneous administration of two or more
+probe drugs.
+Numerous cocktails using concurrent administration of
+several cytochrome P450 (CYP) isoform-selective probe
+drugs have been reported to investigate DDI in vivo , like
+the ‘Inje’ or ‘Cooperstown 5 + 1’ cocktails [1, 2]. This
+approach was successfully used to investigate the effect of
+drugs on various CYP isoforms (e.g. the effect of propiver-
+ine on the activity of intestinal 3A and of hepatic CYP3A,
+CYP2C9, CYP2C19 and CYP1A2 [3]).
+The main advantage is to characterize the inhibitory or
+induction potential of compounds in development toward
+the several CYP enzymes identified in vitro in an in vivo
+situation and therefore have complete in vivo information
+about potential CYP-based drug interactions in the same
+trial.
+Drugs used in such a cocktail should be selective for
+individual CYP isoforms and should not interact with each
+other. This study describes the validation of a new cocktail
+containing five probe drugs for five isoforms: CYP1A2 (caf-
+feine), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6
+(metoprolol) and CYP3A (midazolam).
+The present clinical study was conducted to test for
+pharmacokinetic (PK) interactions between these probe
+drugs by administering them each alone and simulta-
+neously. In addition, the overall safety of this cocktail was
+assessed during the study.
+Materials and methods
+Clinical study design
+A single-centre, open-label, single oral dose study was
+carried out in healthy male subjects in a six-treatment
+six-period six-sequence William’s design with a wash-out
+of 7 days after caffeine, omeprazole, metoprolol and mida-
+zolam treatments and 14 days after cocktail and warfarin
+treatments. The study was conducted at Optimed (Gieres,
+France) in accordance with the ethical principles set forth
+in the Declaration of Helsinki and in compliance with local
+regulations. The protocol was reviewed and approved by
+the Comite Consultatif pour la Protection des Personnes
+dans la Recherche Biomedicale de LYON B. Prior to any
+study procedures, subjects provided written informed
+consent after having received verbal and written informa-
+tion on the procedure and possible hazards and risks of
+the studies.
+Thirty-three subjects met the inclusion/exclusion crite-
+ria of the study. Exclusion criteria included any medication
+or nutraceutical (e.g. St John’s Wort) received within 20
+days prior to the drug administration, or within six times
+the elimination half-life, whichever was longest, except
+occasional use of paracetamol; administration of enzyme-
+inducing or enzyme-inhibiting drugs within 3 months of
+trial initiation; history or presence of drug or alcohol abuse;
+excessive consumption of beverages containing caffeine
+(more than four cups or glasses per day) or unable to stop
+consumption during the hospitalization; smoking more
+than five cigarettes or equivalent per day or not able to
+stop smoking during hospitalization; and grapefruit and
+grapefruit-containing products or orange juice were pro-
+hibited from 48 h prior to each dosing until the last sample
+was taken for each period. CYP2C9, CYP2C19 and CYP2D6
+poor metabolizers were excluded, based on genotyping of
+genomic DNA from blood samples.
+International Normalized Ratio (INR) was monitored
+during the study and subjects were institutionalized until
+INR returned to baseline value /H1100610% or INR < 2 of each
+period with warfarin administration only. In cases where a
+major therapeutic effect was observed (e.g. INR > 5 and/or
+occurrence of haemorrhage) after warfarin or cocktail
+administration, the investigator had the responsibility
+to investigate the appropriateness of administering the
+antidote (vitamin K). If such a case occurred at the first
+warfarin administration, the subject should have been
+excluded from the second study period with warfarin
+administration.
+Subjects, after attending the unit for the laboratory
+value check in the morning, were institutionalized on the
+afternoon the day before administration, until 24 h post
+administration (day 2) of each period.
+Drug, dose and administration route
+On day 1 of each corresponding period, subjects received
+one of the following treatments with 200 ml of water at
+approximately 08.00 h while fasting: caffeine 100 mg (four
+vials of 50 mg of Cafeine Cooper containing 25 mg of caf-
+feine base); warfarin 10 mg (two tablets of 5 mg); omepra-
+zole 20 mg (one capsule of 20 mg); metoprolol 100 mg
+(one coated tablet of 100 mg); midazolam 0.03 mg kg
+–1
+(5 mg/5 ml vials mixed in 120 ml of 5% dextrose in water)
+administered; the cocktail: all five drugs administered
+together in the same doses and conditions. Blood samples
+were collected for 48 h for caffeine, metoprolol and ome-
+prazole, 12 h for midazolam and 312 h for warfarin and the
+cocktail.
+Except for metoprolol, these drugs are all listed as sen-
+sitive substrates in the Food and Drug Administration draft
+guidance. Yet metoprolol is a well-documented CYP2D6
+probe drug. The doses chosen were based on the clinical
+Pharmacokinetic assessment of a five-probe cocktail
+Br J Clin Pharmacol / 68:6 / 929
+tolerability of these drugs and the ability to assess reliably
+their PK parameters. For caffeine, 100 mg was chosen as it
+is approximately the amount found in one cup of coffee.
+For warfarin, in patients 10 mg is often used as a mainte-
+nance dose. For omeprazole, the dose of 20 mg once a
+day is used in the treatment of symptomatic gastro-
+oesophageal reflux disease and duodenal ulcer. For mida-
+zolam, as it has an absolute bioavailability of 74.5%, a dose
+of 0.03 mg kg
+–1 of the intravenous formulation given orally
+should lead to significant systemic exposure without
+major sedative effect [4]. Metoprolol is currently used in
+clinic at a daily dose of 100 mg. This dose allows meto-
+prolol plasma concentrations to be quantified up to 24 h.
+Bioanalytical methods
+Caffeine and its metabolite (paraxanthine), metoprolol and
+omeprazole plasma samples were analysed together, while
+midazolam and R- and S-warfarin plasma concentrations
+were analysed separately. All procedures associated with
+this analysis were conducted following methods previ-
+ously validated by Covance (Indianapolis, IN, USA).
+Regarding caffeine, paraxanthine, metoprolol and
+omeprazole, plasma samples were spiked with an internal
+standard {caffeine-(trimethyl)-
+13C3, theophylline-(2-13C,1-3-
+15N2) [for paraxanthine], metoprolol-d 7(+) tartrate, lanso-
+prazole [for omeprazole]}. The analytes and their internal
+standards were then extracted from human plasma by
+Oasis HLB solid-phase extraction using sodium acetate,
+5% methanol in water. The solid-phase extraction car-
+tridges were subsequently placed on top of an Axygen
+96-well plate and, to finish, 90% methanol in water was
+added to them. Next, the samples were analysed using
+a Sciex API 4000 liquid chromatography coupled with
+tandem mass spectrometry system (LC-MS/MS). Chro-
+matographic separation of the compounds was accom-
+plished using a Genesis C18 column, with 1% acetic acid
+in methanol : water (90:10, v : v) as the mobile phase at a
+flow rate of 1.00 ml min
+–1. The MS/MS system was oper-
+ated using an electrospray in positive ionization mode.
+The precursor-to-product ion reactions monitored are
+presented in Table 1. The lower limit of quantification
+(LLOQ) was 25 ng ml
+–1 for caffeine and paraxanthine and
+5n gm l–1 for metoprolol and omeprazole.
+Regarding midazolam, plasma samples were spiked
+with an internal standard (a-hydroxytriazolam), alkalinized
+with 5% ammonium hydroxide, and extracted with
+methyl-tert-butyl ether. After evaporation of the organic
+solvent under nitrogen, reconstituted residues of the
+organic phase were analysed using a Sciex API 4000
+LC-MS/MS. Chromatographic separation of the com-
+pounds was accomplished using a Chromolith SpeedROD
+RP-18e with 0.15% trifluoroacetic acid in ammonium
+formate and methanol (30:70, v/v) as the mobile phase at a
+flow rate of 1.00 ml min
+–1.The MS/MS system was operated
+using an electrospray in positive ionization mode. For
+midazolam and a-hydroxytriazolam, the precursor-to-
+product ion reactions monitored are presented in Table 1.
+The LLOQ for midazolam was 0.1 ng ml
+–1.
+Finally regarding R- and S-warfarin, plasma samples
+were spiked with an internal standard (R- and S-warfarin-
+d
+6), acidified with 1.0 N sulphuric acid and extracted
+with 5% ethyl acetate in hexane. After evaporation of the
+organic solvent under nitrogen, reconstituted residues of
+the organic phase were analysed using a Sciex API 3000
+negative ion atmospheric pressure chemical ionization
+LC-MS/MS. Chromatographic separation of the com-
+pounds was accomplished using an Astec b-cyclodextrin
+cyclobond I with acetonitrile : acetic acid : triethylamine
+(1000:3:2.5, v:v:v ) a s t h e mobile phase at a flow rate of
+1.00 ml min
+–1. For R- and S-warfarin and R- and S-warfarin-
+d6, the precursor-to-product ion reactions monitored are
+presented in Table 1. The LLOQ for R- and S-warfarin was
+1.0 ng ml
+–1.
+Calibration standards and quality control (QC) samples
+were analysed in at least one batch to determine intra-
+assay precision and mean accuracy, and in a minimum of
+three batches to determine interassay precision and mean
+accuracy. Calibration standards and QC samples were
+interspersed throughout each batch. The accuracy of the
+method was determined by comparing the means of
+the measured concentrations of the calibration standards
+and QC samples with their theoretical concentrations. The
+ranges, interassay precisions and accuracy values for the
+calibration standards are presented in Table 2. The interas-
+say results demonstrated a relative standard deviation for
+calibration standards and QC samples of <13%. The accu-
+Table 1
+Mass transition monitored for each probe and its internal standard
+Drug Transition monitored IS name Transition monitored
+Caffeine 195.1 → 110.1 Caffeine-(trimethyl)- 13C3 198.1 → 140.0
+Paraxanthine 181.1 → 68.9 Theophylline-(2- 13C,1-3-15N2 183.9 → 125.0
+Metoprolol 268.1 → 116.2 Metoprolol-d 7(+) tartrate 275.3 → 122.9
+Omeprazole 346.1 → 198.0 Lansoprazole 370.0 → 252.0
+Midazolam 326.1 → 291.1 a-Hydroxytriazolam 359.1 → 176.1
+R- and S-warfarin 307.1 → 161.0 R- and S-warfarin-d 6 313.1 → 161.0
+S. Turpault et al.
+930 / 68:6 / Br J Clin Pharmacol
+racy results demonstrated calculated deviation of mean
+value from nominal values in the range of –8.0 to 6.9% for
+calibration standards and QC samples.
+For all analytes, no significant interfering peaks were
+detected in matrix blanks.
+Data analysis
+PK parameters of caffeine, paraxanthine, metoprolol,
+midazolam, omeprazole, R-warfarin and S-warfarin were
+determined on day 1 of each treatment period by noncom-
+partmental analysis of plasma concentrations and real
+time values using WinNonlin Professional,Version 4.01.The
+peak plasma concentration ( C
+max), the time to reach Cmax
+(tmax), and time corresponding to the last concentration
+above the limit of quantification ( tlast) were obtained
+directly from experimental observations. The area under
+the plasma concentration–time curve extrapolated to
+infinity (AUC) was calculated according to the following
+equation: AUC = AUC
+last + (Clast/lz), where AUClast was calcu-
+lated using the trapezoidal method from time 0 to the
+real time t
+last. The terminal half-life ( t1/2z) was determined
+according to the following equation: t1/2z = 0.693/lz, where
+lz is the slope of the regression line of the terminal phase
+of the plasma concentration–time curve, on a semi-
+logarithmic scale.
+Statistical analysis
+Transformed pharmacokinetic parameters ( Cmax,A U C last
+and AUC values were log transformed, tmax was rank trans-
+formed and t1/2z values were replaced with lz values) were
+analysed with a linear mixed effects model with fixed term
+for treatment (cocktail and probe alone), sequence and
+period, and random term for subject within sequence,
+parameter = sequence + subject(sequence) + treatment +
+period, fit using SAS PROC MIXED. For C
+max,A U Clast and
+AUC, estimates and 90% confidence intervals (CIs) for the
+ratios of treatments were obtained by computing esti-
+mates and 90% CIs for the differences between treatment
+means within the mixed model framework, and converting
+to ratios by the antilog transformation. Equivalence was
+concluded if the 90% CI for the ratio was entirely within the
+0.80, 1.25 equivalence specifications. For t
+max and t1/2z, dif-
+ferences between treatments were tested for significance
+with P-values from the mixed model analysis of rank tmax
+and lz, respectively.
+Results
+All subjects were healthy White men.The mean age was 26
+years (range 19–35 years). The mean body mass index was
+22.6 kg m
+–2 with a range of 18.2–25.8 kg m –2. Three of the
+33 subjects who participated in the study discontinued
+study treatment, but none for safety-related reasons. Thus,
+30 subjects were available for PK analyses.
+Plots of the mean caffeine, paraxanthine, metoprolol,
+midazolam, omeprazole, R-warfarin and S-warfarin plasma
+concentrations administered alone or concurrently as a
+cocktail are shown in Figure 1.
+PK parameters for caffeine, paraxanthine, metoprolol,
+midazolam, omeprazole and S-warfarin administered
+alone or concurrently as a cocktail are summarized in
+Table 3.
+Geometric mean (%CV) and point estimates (90% CI) of
+the pharmacokinetic parameters of caffeine, paraxanthine,
+metoprolol, midazolam, omeprazole and S-warfarin
+administered alone or concurrently as a cocktail are pre-
+sented in Table 4.
+One subject experienced two adverse events (dizziness
+and headache following caffeine and midazolam adminis-
+tration, respectively) during the study.There were sporadic
+abnormalities in haematology (decreases in haemoglo-
+bin), ECG, and vital sign (minor orthostatic changes in
+heart rate or blood pressure) parameters, but these were
+not clinically relevant and none occurred following cock-
+tail administration. In addition, the mean value of INR in
+this study was <1.5. Only one subject had a value reaching
+the threshold of therapeutic efficacy (INR of 2) on two
+occasions.
+Discussion
+Drugs to be included in a cocktail should meet several
+criteria [5]. Each drug should be a selective substrate for a
+Table 2
+Ranges, interassay precisions and accuracy values for each probe calibration standards
+Drug Calibration range (ng ml –1) Interassay precision (RSD%) Accuracy (DMT%)
+Caffeine 25–20 000 2.9–6.6 -4t o6 . 9
+Paraxanthine 25–20 000 3.7–7.4 -3.5 to 6.3
+Metoprolol 5–2500 2.1–7.3 -1.2 to 1.6
+Omeprazole 5–2 500 3–7.2 -3.2 to 3.5
+Midazolam 0.1–100 2.6–7.6 -4.8 to 2.5
+R-warfarin 1–100 2.8–8.2 -3t o3
+S-warfarin 1–100 2.5–6.3 -1.5 to 1
+Pharmacokinetic assessment of a five-probe cocktail
+Br J Clin Pharmacol / 68:6 / 931
+Time (hours)
+241287643210
+Caffeine plasma concentration
+(ng/mL)
+0
+500
+1000
+1500
+2000
+2500
+3000
+Time (hours)
+241287643210
+Paraxanthine plasma concentration
+(ng/mL)
+0
+200
+400
+600
+800
+1000
+1200
+1400
+1600
+1800
+Time (hours)
+482412876
+81 276
+43210
+43210
+Metoprolol plasma concentration
+(ng/mL)
+0
+20
+40
+60
+80
+100
+120
+140
+160
+Time (hours)
+241287643210
+Midazolam plasma concentration
+(ng/mL)
+0
+2
+4
+6
+8
+10
+12
+Time (hours)
+Omeprazole plasma concentration
+(ng/mL)
+0
+50
+100
+150
+200
+250
+Time (hours)
+S-warfarin plasma concentration
+(ng/mL)
+0
+100
+200
+300
+400
+500
+600
+Caffeine
+Metoprolol
+Omeprazole S-warfarin
+Midazolam
+Paraxanthine
+01224 48 72 96 120 144 168 216 264 312
+Caffeine alone
+Cocktail
+Caffeine alone
+Cocktail
+Omeprazole alone
+Cocktail
+Metoprolol alone
+Cocktail
+Warfarin alone
+Cocktail
+Midazolam alone
+Cocktail
+Figure 1
+Mean (/H11006SD) plasma concentrations for each probe administered alone or concurrently as a cocktail ( n /H1134933)
+S. Turpault et al.
+932 / 68:6 / Br J Clin Pharmacol
+single CYP isoform (i.e. clearance of the probe drug should
+predominantly be due to a single CYP isoform). Drugs
+within a cocktail should not interfere with the metabolism
+and clearance of other drugs in the cocktail. The drugs
+should be safe for trial subjects, readily available and
+straightforward to administer. Assays for quantifying
+probe drugs should be sensitive and rigorous. PK of the
+drugs should be easily interpretable, even with significant
+inhibition or induction of one or more CYP isoforms.
+This new cocktail was designed to overcome potential
+liabilities of other reported cocktails [5]. The probe drugs
+(caffeine, warfarin, omeprazole, metoprolol and mida-
+zolam) were selected to test the five CYP isoforms
+predominantly involved in metabolism of most small-
+molecule drugs [6]. Drugs and doses were carefully
+selected based on described metabolism and PK charac-
+teristics to minimize or eliminate potential interference
+between probes. The probes to be used in this cocktail
+approach were chosen based not only on their CYP speci-
+ficity, but also on their availability on the major global
+markets and recommendations in regulatory guidance.
+The doses selected are commonly used in clinical drug
+interaction trials and thought not to interfere with clear-
+ance of the other probe drugs, which was verified in this
+study. Drugs were administered orally to reflect both liver
+and intestinal activities, which are particularly relevant for
+CYP3A (i.e. midazolam probe).
+Ideally, evaluation of probe drugs would be non-
+invasive, allowing quantification of drug or metabolites in
+urine or breath, but that was not practical with the use of
+drugs selected as probes in this cocktail. Therefore, quan-
+tification of the probe drugs and metabolites in plasma
+was intentional, to overcome potential problems with
+assays utilizing urine, including issues of urine collection
+and interference with quantification due to changes in pH,
+fluid intake or output, or other documented problems.
+For this cocktail, blood samples must be collected in a
+clinical protocol where blood is already drawn to quantify
+concentrations of the new chemical entity and clinical
+chemistry parameters. Bioanalysis of clinical samples to
+quantify concentrations of probe drugs or metabolites
+used to be problematic due to the need for large sample
+sizes, lack of sensitivity and analytical chemical interfer-
+ence between compounds. However, the use of LC-MS/MS
+to quantify drug concentrations eliminated these issues for
+the probe drugs used in this cocktail.
+The aim of our approach was the determination of a
+potential metabolic-based DDI as well as its magnitude.
+That is why we assumed that the determination of the
+AUC, reflecting the clearance, was the best end-point for
+this kind of study. In addition, the CV values of the AUC
+Table 3
+Summary of PK parameters for each probe administered alone or concurrently as a cocktail
+Drug Period nC max (ng ml–1) tmax (h)* AUC last (ng h–1 ml–1) AUC (ng h –1 ml–1) t1/2z (h) tlast (h)*
+Caffeine Alone 30 2390 (559) 0.500 (0.500, 2.00) 21 300 (9 530) NC† NC† 48.0 (12.0, 48.0)
+Cocktail 33 2430 (625) 0.500 (0.500, 48.0) 22 900 (11 500) NC† NC† 48.0 (12.0, 48.0)
+Paraxanthine Alone 30 1230 (684) 4.00 (1.00, 48.0) 28 300 (18 600) NC† NC† 48.0 (48.0, 48.0)
+Cocktail 33 1100 (457) 5.00 (0.500, 48.0) 27 100 (12 500) NC† NC† 48.0 (24.0, 48.0)
+Metoprolol Alone 31 101 (54.2) 2.00 (0.500, 3.00) 449 (303) 494 (321) 2.76 (0.738) 12.0 (4.00, 24.0)
+Cocktail 33 105 (55.7) 1.00 (0.500, 4.00) 445 (344) 510 (383)‡ 3.04 (1.49) 12.0 (2.00, 24.0)
+Midazolam Alone 30 9.43 (2.60) 0.500 (0.500, 1.00) 23.7 (7.96) 25.1 (9.24) 3.33 (0.925) 12.0 (8.00, 12.0)
+Cocktail 33 10.7 (3.58) 0.500 (0.500, 1.00) 26.1 (10.7) 27.0 (11.4)‡ 3.41 (1.19)‡ 12.0 (8.00, 48.0)
+Omeprazole Alone 31 187 (98.0) 2.00 (1.00, 4.00) 368 (250) 396 (263)§ 0.858 (0.313)§ 6.00 (3.00, 8.00)
+Cocktail 33 184 (118) 2.00 (1.00, 3.00) 340 (230) 350 (236) 0.802 (0.224) 6.00 (3.00, 8.00)
+S-warfarin Alone 31 316 (57.0) 12.0 (12.0, 24.0) 16 000 (4 340) 17 200 (4 800) 120 (41.7) 312 (312, 312)
+Cocktail 33 321 (45.5) 12.0 (12.0, 12.0) 16 000 (4 780) 17 400 (4 780)¶ 113 (30.1)¶ 312 (24.0, 312)
+*T abulated values are mean (SD) except for tmax and tlast, where values are median (min, max). †No half-life for caffeine and paraxanthine was calculated due to the rebound
+in plasma concentration at 48 h. This rebound is probably due to ingestion of caffeinated drinks or food, as the subjects were discharged 24 h after the d ose. ‡ n = 31. § n = 28.
+¶n = 32. NC, not calculated; AUC values extrapolated by >30% were excluded from the analysis.
+Table 4
+PK parameter point estimates (90% CI) for each probe
+Drug Parameter n Ratio estimate (90% CI)
+Caffeine Cmax 30 1.03 (0.97, 1.10)
+AUClast 30 1.10 (1.01, 1.20)
+Paraxanthine Cmax 30 0.95 (0.84, 1.08)
+AUClast 30 1.05 (0.89, 1.23)
+Metoprolol Cmax 31 1.06 (0.95, 1.18)
+AUClast 31 0.95 (0.86, 1.05)
+AUC 29 0.97 (0.88, 1.06)
+Midazolam Cmax 30 1.11 (1.02, 1.21)
+AUClast 30 1.08 (0.99, 1.18)
+AUC 29 1.06 (0.98, 1.16)
+Omeprazole Cmax 31 0.99 (0.85, 1.16)
+AUClast 31 0.93 (0.84, 1.04)
+AUC 28 0.91 (0.81, 1.02)
+S-warfarin Cmax 31 1.02 (0.95, 1.09)
+AUClast 31 1.03 (0.99, 1.08)
+AUC 31 1.02 (0.98, 1.07)
+Pharmacokinetic assessment of a five-probe cocktail
+Br J Clin Pharmacol / 68:6 / 933
+parameter are smaller than those found for a single sam-
+pling point, as already reported for Cmax [7]. Moreover the
+European Medicines Agency has recommended assessing
+complete AUCs for the probe drugs in order to estimate
+effects on (oral) clearance. Simpler ratios such as
+metabolite-to-parent drug ratios in urine are usually not a
+satisfactory parameter, as results may have more con-
+founding factors, and as the magnitude of an effect is
+difficult to translate into inhibition or induction potency
+and into treatment recommendations in the Summary of
+Product Characteristics [8].
+These probe drugs were tested to determine their
+utility in a cocktail. Each drug exhibited equivalent PK char-
+acteristics when administered alone or together in the
+cocktail. The lack of interaction between probes indicates
+that this cocktail can be used for the in vivo evaluation of
+metabolism-based DDIs. This cocktail should be useful for
+testing DDI due to CYP inhibition or induction, and could
+be used in various combinations to test five or fewer
+potential interactions, as appropriate.
+Another critical point is the safety of co-administering
+multiple drugs. The safety profile of this Sanofi-Aventis
+cocktail was excellent.
+As with all previously reported cocktails, it should be
+noted that the validation protocol reported here demon-
+strates the lack of interaction of the cocktail in the ‘control’
+state that is without the additional effect of an enzyme
+inducer or inhibitor. The probe drugs and doses in this
+cocktail were chosen to be selective for individual CYP iso-
+forms, with the expectation of no or minimal interference
+between probes [5, 9–17]. However, loss of selectivity of a
+probe drug may be possible if the CYP isoform responsible
+for the metabolism of the probe drug is inhibited by the
+test compound and probe concentrations are elevated.
+Induction of one or more CYP isoforms by the new chemi-
+cal entity could also potentially interfere with interpreta-
+tion of a cocktail drug interaction study. Because of this
+limitation, it may be prudent to consider all positive data
+obtained from any cocktail study as requiring further in
+vivo investigations.
+There were no PK interactions between the probe
+drugs, caffeine (CYP1A2), warfarin (CYP2C9), omeprazole
+(CYP2C19), metoprolol (CYP2D6) or midazolam (CYP3A)
+when administered in combination as a cocktail, relative to
+the probes administered alone. The safety profile of this
+cocktail was excellent. The lack of interaction between
+probes indicates that this cocktail could be used for in vivo
+evaluation of the potential DDIs involving multiple CYP
+isoforms.
+Competing interests
+None to declare.
+REFERENCES
+1 Chainuvati S, Nafziger AN, Leeder JS, Gaedigk A, Kearns GL,
+Sellers E, Zhang Y, Kashuba ADM, Rowland E, Bertino JS.
+Combined phenotypic assessment of CYP1A2, CYP2C9,
+CYP2C19, CYP2D6, CYP3A, NAT2 and XO with the
+Cooperstown 5+1 Cocktail. Clin Pharmacol Ther 2003; 74:
+437–47.
+2 Ryu JY, Song IS, Sunwoo YE, Shon JH, Liu KH, Cha IJ, Shin JG.
+Development of the ‘Inje Cocktail’ for high-throughput
+evaluation of five human cytochrome P450 isoforms in vivo.
+Clin Pharmacol Ther 2007; 82: 531–40.
+3 Tomalik-Scharte D, Jetter A, Kinzig-Schippers M, Skott A,
+Sörgel F, Klaassen T, Kasel D, Harlfinger S, Doroshyenko O,
+Frank D, Kirchheiner J, Bräter M, Richter K, Gramatté T,
+Fuhr U. Effect of propiverine on cytochrome P450 enzymes:
+a cocktail interaction study in healthy volunteers. Drug
+Metab Dispos 2005; 33: 1859–66.
+4 Schwagmeier R, Alincic S, Striebel HW. Midazolam
+pharmacokinetics following intravenous and buccal
+administration. Br J Clin Pharmacol 1998; 46: 203–6.
+5 Zhou H, Tong Z, McLeod JF. ‘Cocktail’ approaches and
+strategies in drug development: valuable tool or flawed
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+6 Guengerich FP. Cytochromes P450, drugs, and diseases. Mol
+Interv 2003; 3: 194–204.
+7 Yuen KH, Wong JW, Yap SP, Billa N. Estimated coefficient of
+variation values for sample size planning in bioequivalence
+studies. Int J Clin Pharmacol Ther 2001; 39: 37–40.
+8 Efficacy working party: questions and answers on the use of
+Cocktail studies for investigating in vivo drug interaction
+potential. EMEA/CHMP/EWP/490784/2007.
+9 Andersson T, Miners J-O, Tassaneeyakul W, Veronese ME,
+Meyer UA, Birkett DJ. Identification of human liver
+cytochrome P450 isoforms mediating omeprazole
+metabolism. Br J Clin Pharmacol 1993; 36: 521–30.
+10 Andersson T, Bredberg E, Lagerstrom PO, Naesdal J, Wilson I.
+Lack of drug–drug interaction between three different
+non-steroidal anti-inflammatory drugs and omeprazole. Eur
+J Clin Pharmacol 1998; 54: 399–404.
+11 Andersson T, Lundborg P, Regårdh CG. Lack of effect of
+omeprazole treatment on steady-state plasma levels of
+metoprolol. Eur J Clin Pharmacol 1991; 40: 61–5.
+12 Andersson T, Bergstrand R, Cederberg C, Eriksson S,
+Lagerström PO, Skånberg I. Omeprazole treatment does not
+affect the metabolism of caffeine. Gastroenterology 1991;
+101: 943–7.
+13 Li G, Klotz U. Inhibitory effect of omeprazole on the
+metabolism of midazolam in vitro. Arzneimittelforschung
+1990; 40: 1105–7.
+14 McGourty JC, Silas JS, Lennard MS, Tucker GT, Woods HF.
+Metoprolol metabolism and debrisoquine oxidation
+polymorphism—population and family studies. Br J Clin
+Pharmacol 1985; 20: 555–66.
+15 Schmider J, Brockmöller J, Arold G, Bauer S, Roots I.
+Simultaneous assessment of CYP3A4 and CYP1A2 activity in
+vivo with alprazolam and caffeine. Pharmacogenetics 1999;
+9: 725–34.
+S. Turpault et al.
+934 / 68:6 / Br J Clin Pharmacol
+16 Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ,
+Slaughter DE, Arison BH, Vyas KP. In vitro metabolism of
+simvastatin in humans [SBT] identification of metabolizing
+enzymes and effect of the drug on hepatic P450s. Drug
+Metab Dispos 1997; 25: 1191–9.
+17 Streetman DS, Bleakley JF, Kim JS, Nafziger AN, Leeder JS,
+Gaedigk A, Gotschall R, Kearns GL, Bertino JS Jr. Combined
+phenotypic assessment of CYP1A2, CYP2C19, CYP2D6,
+CYP3A, N-acetyltransferase-2, and xanthine oxidase with
+the ‘Cooperstown cocktail’. Clin Pharmacol Ther 2000; 68:
+375–83.
+Pharmacokinetic assessment of a five-probe cocktail
+Br J Clin Pharmacol / 68:6 / 935

papers/PKDB00091.md

@@ -0,0 +1,16 @@
+# Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.
+
+Z R Chen, A A Somogyi, G Reynolds, F Bochner
+
+*British journal of clinical pharmacology* (1991)
+
+PMID: 2049245
+DOI: 10.1111/j.1365-2125.1991.tb05550.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine-6-glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h. 3. The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in the seven extensive metabolisers and 8 ml min-1 in the poor metaboliser; to norcodeine the values were 103 +/- 33 ml min-1 and 90 ml min-1; to codeine-6-glucuronide the values were 914 +/- 129 ml min-1 and 971 ml min-1; and intrinsic clearance was 1568 +/- 103 ml min-1 and 1450 ml min-1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)

papers/PKDB00091.pdf

@@ -0,0 +1,3 @@
+version https://git-lfs.github.com/spec/v1
+oid sha256:7843613fbc75e485b4ee97f85ffc1f023fc89e96eaecec02803c17ff4c208f02
+size 1794965

papers/PKDB00091.txt

@@ -0,0 +1,942 @@
+Br.J.clin.Pharmac.(1991),31,381-390
+Dispositionandmetabolismofcodeineaftersingleandchronic
+dosesinonepoorandsevenextensivemetabolisers
+Z.R.CHEN',A.A.SOMOGYI"2,G.REYNOLDS3&F.BOCHNER'2
+'DepartmentofClinicalandExperimentalPharmacology,UniversityofAdelaide,2DepartmentofClinicalPharmacology,
+RoyalAdelaideHospitaland3SchoolofChemicalTechnology,SouthAustralianInstituteofTechnology,Adelaide,
+Australia
+1 Thepharmacokinetics,metabolismandpartialclearancesofcodeinetomorphine,
+norcodeineandcodeine-6-glucuronideaftersingle(30mg)andchronic(30mg8hfor
+sevendoses)administrationofcodeinewerestudiedineightsubjects(sevenextensive
+andonepoormetaboliserofdextromethorphan).Codeine,codeine-6-glucuronide,
+morphineandnorcodeineweremeasuredbyhighperformanceliquidchromato-
+graphicassays.
+2 Afterthesingledose,thetimetoachievemaximumplasmacodeineconcentrations
+was0.97±0.31h(mean±s.d.)andforcodeine-6-glucuronideitwas1.28±0.49h.
+TheplasmaAUC ofcodeine-6-glucuronidewas15.8±4.5timeshigherthanthatof
+codeine.TheAUCofcodeineinsalivawas3.4±1.1timeshigherthanthatinplasma.
+Theeliminationhalf-lifeofcodeinewas3.2±0.3handthatofcodeine-6-glucuronide
+was3.2±0.9h.
+3 Therenalclearanceofcodeinewas183±59mlmin-1andwasinverselycorrelated
+withurinepH(r=0.81).Thesedatasuggestthatcodeineundergoesfiltrationatthe
+glomerulus,tubularsecretionandpassivereabsorption.Therenalclearanceof
+codeine-6-glucuronidewas55±21mlmin-',andwasnotcorrelatedwithurinepH.Its
+bindingtohumanplasmawaslessthan10%.Thesedatasuggestthatcodeine-6-
+glucuronideundergoesfiltrationattheglomerulusandtubularreabsorption.This
+latterprocessisunlikelytobepassive.
+4 Afterchronicdosing,thepharmacokineticsofcodeineandcodeine-6-glucuronide
+werenotsignificantlydifferentfromthesingledosepharmacokinetics.
+5 Afterthesingledose,86.1±11.4%ofthedosewasrecoveredinurine,ofwhich59.8±
+10.3%wascodeine-6-glucuronide,7.1±1.1%wastotalmorphine,6.9±2.1%was
+totalnorcodeineand11.8±3.9%wasunchangedcodeine.Theserecoverieswerenot
+significantlydifferent(P>0.05)afterchronicadministration.
+6 Afterthesingledose,thepartialclearancetomorphinewas137±31mlmin-.inthe
+sevenextensivemetabolisersand8mlmin-'inthepoormetaboliser;tonorcodeine
+thevalueswere103±33mlmin-1and90mlmin-1;tocodeine-6-glucuronidethe
+valueswere914±129mlmin-'and971mlmin-';andintrinsicclearancewas1568±
+103mlmin-1and1450mlmin-1.Thesevalueswerenotsignificantly(P>0.05)altered
+bychronicadministration.Inthesevenextensivemetabolisersthevaluesofpartial
+clearancetomorphinewerenotsignificantly(P> 0.05)differentfromthoseto
+norcodeine.
+7 Theusefulnessofmeasuringpartialclearanceswasillustratedbythedetectionofthe
+pooroxidativemetabolisertomorphine,whereasthemeasurementofparentcom-
+poundinplasmadidnotidentifythisimportantmetabolicdefect.
+8 Poormetabolisersofcodeinemaynotderiveanyofthepharmacologicaleffects
+associatedwithcodeine.
+Correspondence:ProfessorF.Bochner,DepartmentofClinical&ExperimentalPharmacology,UniversityofAdelaide,G.P.OBox498,
+Adelaide5001,Australia
+381
+ADONIS030652519100075X
+382 Z.R.Chenetal.
+Keywordscodeinedispositioncodeine-6-glucuroniderenalclearances
+morphinenorcodeinepartialclearancespharmacogenetics
+Introduction
+Codeineisawidelyusedanalgesic,antitussiveandanti-
+diarrhoealdrug,andhasbeenavailableformorethan
+100years(Jaffe& Martin,1985).Afteradministration
+toman,itismetabolisedby0-andN-demethylationand
+glucuronidation(Adler,1954;Adleretal.,1955;Nomof
+etal.,1977;Oberst,1941;Yueetal.,1989a,b)(Figure
+1).The0-demethylationstepisofparticularimport-
+ance,sinceitresultsintheformationofmorphine,the
+currentlyacceptedanalgesicmoiety(Jaffe& Martin,
+1985).Thepharmacokineticsofcodeineinmanhave
+beenstudiedbyseveralinvestigators(Findlayetal.,
+1977,1978,1986;Guayetal.,1987,1988;Quidingetal.,
+1986;Rogersetal.,1982).However,thereareproblems
+intheinterpretationofthedataderivedfromthese
+studies.Firstly,allthestudiesexceptone(Quidingetal.,
+1986)werebasedonthesameradioimmunoassay(r.i.a.)
+(Findlayetal.,1977)fortheestimationofplasma
+codeineandmorphineconcentrations.Whilstthecross-
+reactivityofthisassayforcodeinemetaboliteswaslow,
+thehighcirculatingcodeine-6-glucuronideconcentra-
+tions(videinfra)maywellcausespuriouslyhighplasma
+andurinecodeineconcentrations.Previousdatafor
+morphine,basedonr.i.a.,havebeenshowntobeunre-
+liablewhencomparedwithdataobtainedwithspecific
+highperformanceliquidchromatographic(h.p.l.c.)
+assays(Aherne& Littleton,1985;Hanks& Aherne,
+1985).Secondly,inallstudiestodate,codeine-6-
+glucuronide,a potentiallyimportantmetaboliteof
+codeine,byanalogywiththepharmacologicallyactive
+morphine-6-glucuronide(Osborneetal.,1988;Paster-
+naketal.,1987;Yoshimuraetal.,1973),wasnotdeter-
+mineddirectly.Theconcentrationsofcodeine-6-
+glucuronideinplasmawereestimatedbyanalysing
+codeineafter3-glucuronidasehydrolysis(Findlayet
+al.,1977,1978,1986;Guayetal.,1987,1988;Rogerset
+al.,1982).Itisknown,however,that13-glucuronidase
+cannotcompletelyhydrolysecodeine-6-glucuronide
+(Axelrod&Inscoe,1960;Boddetal.,1987;Chenetal.,
+1989b;Guayetal.,1988;Yoshimuraetal.,1968).The
+concentrationsofcodeine-6-glucuronideintheprevious
+studiesmaythereforehavebeenunder-estimated.
+Thirdly,singleandchronicdosepharmacokineticsof
+codeineandthederivedcodeine-6-glucuronidehavenot
+beencomparedadequately.Quidingandcoworkers
+(1986)comparedthepharmacokineticsofcodeineafter
+singleandchronicdosingof60mg,butlittleinformation
+couldbeobtainedfromthesingledosepharmacokin-
+eticsbecausethesamplingperiodwasonly2.8h.Whilst
+Guayandcoworkers(1987)collectedbloodsamplesfor
+24h,ther.i.a.usedandhydrolysisby,3-glucuronidase
+makethedatafromtheirstudydifficulttointerpret.
+Nevertheless,theyfoundnodifferencesbetweenthe
+codeine
+CH30
+0
+HN-CH3H
+HO
+4N-CH3
+morphine
+CH30 ,
+ N-CH3
+COOH ~
+OH~~~
+OH codeine-
+OH 6-glucuronide
+morphine-3-glucuronide
+morphine-6-glucuronide
+Figure1 Metabolicpathwaysofcodeine.
+CH30
+NH
+. H
+norcodeine
+norcodeine-6-gucuronide
+HO
+If
+Dispositionandmetabolismofcodeine383
+areasundertheplasmaconcentration-timecurvesof
+codeineand'codeineglucuronide'aftersingleand
+chronicadministration,butfoundasignificantincrease
+intheareaundertheplasmaconcentration-timecurveof
+morphineafterchronicdosing.Fourthly,thereislittle
+informationregardingthemechanism(s)oftherenal
+clearanceofcodeineandcodeine-6-glucuronidebecause
+mostofthepreviousinvestigatorscollectedblood
+samplesonly.
+Weandothers(Chenetal.,1988a;Dayeretal.,1988;
+Yueetal.,1989b)haveshownthattheO-demethylation
+ofcodeinetomorphineisundergeneticcontrolandco-
+segregateswiththedebrisoquine/sparteineoxidative
+polymorphism.Invivopharmacogeneticstudiesof
+codeinemetabolismhavereliedondeterminingthe
+metabolicratiobymeasuringthemetabolitesandparent
+compoundinurine.Thisapproachprovidesonlylimited
+insightintoaperson'scapacitytoeliminatecodeine
+throughitsvariousmetabolicpathways.Partialclear-
+anceratesareconsideredtobebetterindicesofinvivo
+drugmetabolism(Jacksonetal.,1986).
+Theobjectivesofthepresentstudyweretodetermine
+thepharmacokineticsofcodeineandcodeine-6-glucu-
+ronideandthemetabolismandpartialclearancesof
+codeineinhuman(onepoorandsevenextensivemeta-
+bolisers)subjectsgivensingleandchronicoraldosesof
+codeineandusingsensitiveandspecificanalytical
+methods.
+Methods
+Subjects
+Eighthealthysubjects,sevenmaleandonefemale,
+participatedinthestudy,whichwasapprovedbythe
+HumanEthicsCommitteeoftheRoyalAdelaideHos-
+pitalandtheCommitteeontheEthicsofHumanExperi-
+mentationoftheUniversityofAdelaide.Thesubjects
+wereaged27.3±5.2(mean±s.d.,range25-37)years
+andweighed67.9±11.9(range48-83)kg.Theywerein
+goodhealthasjudgedbyphysicalandlaboratoryexam-
+inations.Foursubjectssmokedcigarettes.Otherdrugs
+andalcoholwereprohibitedfor2daysbeforecodeine
+administrationandforthedurationofthestudy.The
+oxidativephenotypeofthesesubjectswasdetermined
+fourweeksafterthecompletionofthestudy,using
+dextromethorphanasthemodeldrug(Chenetal.,1990).
+Subject2wasapoormetaboliser(metabolicratio=
+0.38)andtheremainderwereextensivemetabolisers
+(metabolicratio= 160-3460).
+Studydesign
+SingledoseAfteranovernightfast,eachsubjectre-
+ceivedasingle30mgcodeinephosphatetablet(Fawns&
+McAllan,Croydon,Australia)followedby100mlof
+water.Foodandfluidwerepermittedafter3h.The
+subjectswereambulantbutconfinedtothelaboratory
+forthe12hofsampling.Venousbloodsamples(10ml)
+werecollectedthroughanindwellingcatheterkept
+patentwithastylet(JelcoTm,CritikonInc.,Tampa,
+USA),placedinaforearmvein,intoheparinizedplastic
+tubesat0,0.25,0.5,0.75,1,1.25,1.5,2,3,4,6,8and12
+hafteradministration.Atthesametimes,mixedsaliva
+samples(3ml)werecollectedbychewingParafilmv.
+Allurinewascollectedin0-12,12-24,and24-48h
+aliquotsafterdosing.
+ChronicdosingThesecondpartofthestudywascon-
+ductedinthesamesubjects2to3weeksaftercomple-
+tionofthesingledosestudy.Subjectsreceived30mg
+codeinephosphateastabletsfromthesamebatchas
+above8hourly(08.00,16.00,24.00h)forsevendoses.
+Thefinaldosewasgivenat08.00honday3afteran
+overnightfast.Bloodandsalivasampleswerecollected
+at0,0.25,0.5,0.75,1,1.25,1.5,2,4,6and8hafterthe
+lastdoseandurinewascollectedoverthedosinginterval
+(0-8h).Plasmawasseparatedfrombloodcellsbycentri-
+fugation.UrinepHandvolumewererecordedandan
+aliquot(10ml)retainedforanalysis.SalivapH was
+recorded.Allsampleswerestoredinstopperedvialsat
+-20°Cuntilanalysis.
+Druganalysisinbiologicalfluids
+Unconjugatedcodeine,norcodeineandmorphineThese
+weremeasuredinurine,plasma(codeineonly)and
+saliva(codeineonly)byanh.p.l.c.method(Chenetal.,
+1989a).Thelimitofassaywas2ngml-1formorphine
+(7.0nmoll-1),norcodeine(7.0nmoll-1)andcodeine
+(6.7nmol1-1)inplasma.
+Codeine-6-glucuronideCodeine-6-glucuronideinplas-
+maandurinewasmeasureddirectlyusinganh.p.l.c.
+assay(Chenetal.,1989b).Theassaywasalsoappliedto
+salivasamples.Thelimitofassaywas10ngml-'(21
+nmol-1)forplasmaand0.1,gml-l(0.21,umol-1)for
+urine.
+MorphineglucuronidesMorphine-3-and-6-glucuron-
+idesinurineweremeasureddirectlyusingamodified
+h.p.l.c.method(Chenetal.,1989b;Svenssonetal.,
+1982).Thecolumn(150x4.6mm i.d.)waspackedwith
+Spherisorb(5,umODS-2,PhaseSeparations,Queens-
+ferry,U.K.).Themobilephasecomprised26%(v/v)
+acetonitrilein10mm phosphatebuffer(pH2.1)con-
+taining1mMdodecylsulphate.Theflowratethrough
+thecolumnwas1mlmin-'.Theexcitationandemission
+wavelengthsofthefluorescencedetector(LS-5lumines-
+cencespectrometer,Perkin-Elmer,Beaconsfield,U.K.)
+were230and350nm,respectively.Theurinesample
+wastreatedinthesamemannerasdescribedforplasma
+codeine-6-glucuronide(Chenetal.,1989b)exceptthat
+theinternalstandardwasnormorphine,whichitself
+couldnotbedetected(lessthan0.1,ugml-l)intheurine
+ofanyofthesubjectsfollowingbothdosageregimens.
+Thelimitofassayformorphine-3-glucuronideand
+morphine-6-glucuronidewas0.1,ugml-'inurine.
+NorcodeineconjugatesThepresenceofconjugatesof
+norcodeineinurinewasinferredbythegenerationof
+norcodeinefollowingenzymatichydrolysis.Theinternal
+standard(dihydrocodeine)wasaddedtourinesamples
+(0.3ml)in10mlscrewcappedtubes.,B-glucuronidase
+fromHelixpomatiatypeH-1(SigmaChemicalCo.,St
+384 Z.R.Chenetal.
+Louis,MO.,USA)wasadded(0.5mlofa5000uml-'in
+pH 5.0acetatebuffer),followedbyincubationina
+shakingwaterbathat370C for16h.Sampleswere
+analysedfornorcodeinebythemethoddescribedabove
+forunconjugatednorcodeine(Chenetal.,1989a).
+Creatinineanalysis
+Creatinineconcentrationsinplasmaandurinewere
+measuredbyanh.p.l.c.method(Huang& Chiou,1983).
+Thecoefficientsofvariationofallassaysintermsof
+reproducibilityandaccuracywerelessthan10%.
+Proteinbindingofcodeine-6-glucuronide
+Drug-freeplasmawasspikedwithcodeine-6-glucuronide
+toachieveconcentrationsof210,525,1050,2100and
+10500nmol1-1andmixedfor10minat370C.Aliquots
+(1ml)ofthesampleswere thencentrifugedusinga
+CentrifreeTM(AmiconCorporation,Danvers,MA,
+USA)ultrafiltrationunitat2000gfor30minat37°C.
+Aqueoussolutionsofcodeine-6-glucuronideinthesame
+concentrationsweretreatedinthesame way.Aliquots
+oftheultrafiltratewere analysedforcodeine-6-glucu-
+ronidebyh.p.l.c.(Chenetal.,1989b).Theunbound
+fractionofcodeine-6-glucuronidewascalculatedasthe
+concentrationoftheultrafiltrateintheplasmasample
+dividedbytheultrafiltrateconcentrationintheaqueous
+sample(toexcludenonspecificbinding).
+Pharmacokineticandstatisticalanalyses
+Theconcentrationsofcodeineinsalivaup to1hafter
+administrationwere notincludedinthecalculationsof
+thepharmacokineticdata,becauseoflikelyretentionof
+partoftheoraldoseinthemouthduringthistime
+period.
+Themaximumplasmaconcentration(Cmax)andits
+timeofoccurrence(tmax)were determinedfromthe
+observeddata.Theeliminationrateconstant(X,)was
+calculatedfromtheslope(x2.303)oftheterminal
+portionofthesemilogarithmicplasmaconcentration-
+timecurveusinglinearregressionanalysis.Thearea
+undertheplasmaorsalivaconcentration-timecurvesto
+thelastsamplingtimefollowingthesingledose(AUC
+(0,12))andtheinterdosingintervalatsteadystateafter
+multipledosing(AUCSS)wascalculatedbythelinear
+trapezoidalruleandthetotalAUC forthesingledose
+wascalculatedas:
+AUC = AUC(0,12)+ C(12)/XzPorCsal(12)/Xzsal
+whereC(12)andCsal(12)aretheplasmaandsaliva
+concentrationsat12hrespectively.Half-lives(t,/2,z)in
+plasmaandsalivawerecalculatedas:
+t½/2,z= 0.693/XzporAzsal
+Renalclearance(CLR)wascalculatedas:
+CLR= Ae(tl,t2)/AUC(tl,t2)
+whereAe(tl,t2)istheamountexcretedunchangedover
+theurinecollectioninterval(0-12hsingledoseand0-8
+hchronicdosing).Partialmetabolicclearances(CLm)ofcodeinetoits
+measurablemetabolites(morphine,norcodeine,
+codeine-6-glucuronide)werecalculatedas:
+CLm= Ae/AUCorAe/AUC,s
+whereformorphine,Aeisthesum(inmols)ofmorphine,
+morphine-3-glucuronideandmorphine-6-glucuronide
+excretedinurine;fornorcodeine,Aeisthesum of
+norcodeineandnorcodeineconjugatesinurineandfor
+codeine-6-glucuronide,Aeistheamountofthismeta-
+boliteinurine.Intrinsicclearancewas calculatedas
+dose/AUC(singledose)ordose/AUC,,(chronicdosing).
+Differencesinpharmacokineticdatabetweentreat-
+mentswereanalysedforstatisticalsignificancebythe
+pairedt-test.Statisticalsignificancewasassumedwhen
+P < 0.05.Linearregressionanalysiswasalsoused.All
+dataaretabulatedasmean ± s.d.
+Results
+Codeine
+Themeanplasmaandsalivacodeineconcentration-time
+profilesineightsubjectsfollowingsingleandchronic
+oraldosesareshowninFigure2.Tables1and2contain
+thederivedpharmacokineticparametersofcodeine
+aftersingleandchronicdosing,respectively.Themean
+tmaxoccurredinabout1hafterbothsingleandchronic
+dosing(P> 0.05).Themean plasmaCmaxofcodeine
+Table1 Pharmacokineticparametersofcodeineafterasingle30mgoraldose
+t½x,,z(h) AUC(nmol11h)
+Cmax tmax CLR *feSubject plasma saliva (nmolI-') (h) plasma saliva (mlmin') (%)
+1 3.22 2.82 226 0.75 789 1926 178 11.1
+2# 2.77 2.74 274 0.50 876 3665 157 10.8
+3 3.63 3.11 138 1.00 816 2019 67 4.3
+4 3.17 3.19 159 1.00 722 2601 167 9.5
+5 2.81 3.18 186 1.25 856 2539 208 14.0
+6 3.15 2.98 172 0.75 809 3062 260 16.6
+7 3.60 2.72 142 1.50 886 2422 189 13.2
+8 3.59 4.13 160 1.00 813 1726 238 15.2
+Mean 3.24 3.11 182 0.97 821 2495 183 11.8
+s.d. 0.34 0.45 46 0.31 53 638 59 3.9
+*fe:% ofdoseexcretedunchangedinurine.
+#poormetaboliser.
+Dispositionandmetabolismofcodeine385
+a
+10
+=
+E
+ C._
+c
+c0
+cJ
+ Cu
+10o
+b
+Time(h)
+Figure2 Means± s.d.plasmacodeine(O)andcodeine-6-glucuronide(0)concentrationsafterasingle30mg dose(a)and
+30mg 8hforsevendoses(b)ofcodeinephosphate.
+afterchronicdosingwas significantlyhigherthanthat
+aftersingledosing(P< 0.05).Themean elimination
+half-livesdeterminedfromplasmaandsalivaaftersingle
+andchronicdosingwere notsignificantlydifferent.
+Therewere no differencesbetweenthehalf-livesof
+codeineafterthetwotreatments.Themean plasma
+codeineAUC forthesingledosewas notsignificantly
+differentfromthatduringthedosingintervalatsteady
+state.Themean salivacodeineAUC forthesingledose
+wassignificantlylowerthanthatfollowingchronicdosing
+(P< 0.05).ThesalivatoplasmacodeineAUC ratios
+aftersingleandchronicdosingwere2.95± 0.72and3.75
+± 1.38,respectively(P< 0.05).Therewas apositive
+correlationbetweensalivaandplasmacodeineconcen-
+trations(r= 0.80,P < 0.01;Figure3)andaninverse
+correlation(r= 0.83,P < 0.01)betweenthesaliva
+codeineAUC andsalivapH.
+Codeine-6-glucuronide
+Themean plasmacodeine-6-glucuronideconcentration-
+timeprofilesaftersingleandchronicdosingareshownin
+Figure2.Table3containsthederivedpharmacokinetic
+parametersafterbothdosingregimens.Therewas no
+differenceintheplasmatmaxbetweencodeine-6-glucu-
+ronideandcodeine(P> 0.05)andforcodeine-6-glucu-
+ronidetherewas no significantdifferenceinthispara-
+meterbetweensingleandchronicdosing.Theelimination
+half-livesofcodeine-6-glucuronideaveraged3.2± 0.9h
+aftersingledosingand3.3± 0.6hafterchronicdosing
+andwerenotsignificantlydifferentfromthatofcodeine.
+Themean plasmaAUC ofcodeine-6-glucuronideafter
+thesingledosewas notsignificantlydifferentfromthat
+duringthedosingintervalatsteadystate.Themean
+plasmaAUC ofcodeine-6-glucuronideafterthesingle
+Table2 Pharmacokineticparametersofcodeineafter30mg8hourlyorallyforsevendoses
+t½z(h) AUCSS(nmol1-1h)
+Cmax tma CLR *fe
+Subject plasma saliva (nmol1-1) (h) plasma saliva (mlmin-') (%)
+1 3.13 3.81 239 0.75 792 1775 191 11.9
+2# 3.37 3.29 291 1.25 1054 5919 201 16.7
+3 3.25 2.84 243 0.75 786 2224 250 15.4
+4 2.78 2.20 223 0.75 930 4739 219 16.0
+5 2.63 2.35 228 1.00 786 3592 100 6.2
+6 2.44 2.39 293 1.25 846 3926 246 16.3
+7 2.91 2.48 265 0.75 1120 3288 265 23.4
+8 2.68 2.17 265 0.75 913 1900 110 7.9
+Mean 2.90 2.69 **256 0.91 903 **3421 198 14.2
+s.d. 0.33 0.59 27 0.23 127 1451 63 5.5
+*fe:% ofdoseexcretedunchangedinurine.**significantlydifferent(P<0.05)fromsingledose(Table1).
+#poormetaboliser.
+386 Z.R.Chenetal.
+Table3 Pharmacokineticparametersofcodeine-6-glucuronideaftersingleandchroniccodeinedosing
+t½hz(h) Cmax(,umol1-i) tmax(h) *AUC(,mol1-1h) CLR(mlmin-')Subject S C S C S C S C S C
+1 2.95 4.43 3.23 2.57 1.25 1.00 12.98 12.27 57.1 74.7
+2# 2.31 3.16 4.12 3.37 0.75 1.00 15.62 13.55 54.6 64.0
+3 3.57 2.31 1.75 2.21 1.00 1.00 8.06 7.96 101.0 111.2
+4 2.75 3.12 2.78 2.54 2.00 2.00 15.42 12.14 32.3 46.5
+5 2.39 3.06 3.64 2.98 2.00 0.75 15.18 11.74 52.9 51.7
+6 4.71 3.39 2.13 2.78 1.25 1.25 14.11 11.74 59.6 54.6
+7 4.32 3.43 2.13 2.77 1.25 1.00 24.78 12.61 36.2 53.8
+8 2.76 3.23 3.43 3.89 0.75 1.00 13.44 14.01 45.6 32.2
+Mean 3.22 3.27 3.03 2.89 1.28 1.13 14.95 12.00 54.9 61.1
+s.d. 0.89 0.58 0.78 0.53 0.49 0.38 4.66 1.83 21.0 23.7
+S:singlecodeinedose;C:chroniccodeinedosing.
+*:AUC =AUC(0,oo)(singledose)orAUCS.(chronicdosing).
+#poormetaboliser
+andchronicdosingwas15.8± 4.5timesgreaterthan
+thatofcodeine.Theunboundfractionofcodeine-6-
+glucuronideinplasmawas0.92± 0.06(n= 10)at
+concentrationsbetween210and10500nmol1-1.
+Codeine-6-glucuronidewasnotdetectedinsaliva.
+Renalclearance
+Therenalclearancesofcodeineandcodeine-6-glucu-
+ronidewerenotsignificantlydifferentbetweensingle
+andchronicdosing(P>0.05,Tables1,2and3).There
+wasastatisticallysignificantinverserelationshipbetween
+urinepHandrenalcodeineclearance(r= 0.81,P<
+0.01)butnosuchrelationshipoccurredforcodeine-6-
+glucuronide(r=0.08,P >0.05)(Figure4).Therewas
+nosignificant(P> 0.05)correlationbetweenrenal
+clearanceandurineflowrateforbothcodeine(r=0.35)
+andcodeine-6-glucuronide(r= 0.03).Thecreatinine
+clearanceintheeightsubjectsrangedfrom90to132ml*i-1mmn
+Urinaryexcretion
+Theurinaryrecoveryofcodeine,norcodeine,morphine
+andtheirconjugatesasapercentageoftheadministered
+doseintheeightsubjectsaftersingleandchronicdosing
+isshowninTable4.Therewerenostatisticallysignifi-
+cantdifferences(P> 0.05)afterthesingledoseand
+duringchronicdosingatsteadystate.
+Partialclearance
+Thepartialmetabolicclearanceofcodeinetoeach
+metabolitewasnotsignificantlydifferent(P> 0.05)
+aftersingleandchronicadministration(Table5).The
+partialclearancetomorphineshowedthewidestinter-
+individualvariationfrom5to190mlmin-1.Insubject2,
+whohadthelowesturinaryrecoveriesofmorphineand
+morphineglucuronides(Table4),theclearanceof
+codeinetomorphinewassubstantiallylowerthaninthe
+300r
+1000r-
+8001
+Ec
+c
+0
++o
+L-
+Cu
+c
+0C.)
+CcJ
+0
+C._
+0
+0C.,
+Cu
+CuC,
+600-
+400-
+2001
+ .
+E
+a)
+E
+CU)
+* .U% a
+*.u:.* *U-
+ a 8*
+I a
+IVu-
+0 50 100 150 200 250
+Plasmacodeineconcentration(nmoll-1)
+Figure3 Correlationbetweenplasmaandsalivacodeine
+concentrations(r= 0.80,P< 0.01).
+2001-
+0 0
+L' o00
+0o0
+0
+A 0
+A
+IAAA A AA A A A
+100l
+u. . I I I *
+4 5
+0
+0
+A
+A
+6 7
+UrinepH
+Figure4 Correlationbetweentherenalclearancesofcodeine
+(o),codeine-6-glucuronide(Ak)andurinepH.Forcodeiner=
+0.81(P< 0.01)andforcodeine-6-glucuronider=0.08
+(P>0.05).
+u,
+.
+a
+.
+% 0 0
+8 or a
+0
+0 a a0
+s
+0 0 a
+a
+r) I I
+Dispositionandmetabolismofcodeine387
+Table4 Urinaryexcretionofcodeineandmetabolitesas% ofdoseaftersingleandchronicoralcodeineadministration
+Codeine C-6-G Morphine M-3-G M-6-G Norcodeine N-C Total
+Subject S C S C S C S C S C S C S C S C
+1 11.111.9 58.472.1 0.30.6 5.7 2.9 1.80.9 3.71.9 7.21.7 89.992.0
+3 4.315.4 64.069.8 0.70.7 4.3 5.1 0.70.6 1.53.7 6.92.2 82.997.5
+4 9.516.0 40.444.5 0.90.4 5.4 8.5 1.20.4 0.93.2 4.51.3 63.374.3
+5 14.06.2 63.047.8 1.00.2 6.7 3.7 1.90.1 5.42.4 1.13.4 93.463.8
+6 16.616.3 66.350.5 0.40.6 6.6 9.8 1.21.4 4.74.5 2.44.2 99.187.3
+7 13.223.4 70.553.4 1.00.9 4.4 6.9 1.00.8 3.84.4 1.82.5 95.892.3
+8 15.27.9 48.435.6 1.31.0 7.410.7 2.11.9 2.82.1 1.81.1 79.660.3
+Mean 12.013.9 58.753.4 0.80.6 5.8 6.8 1.40.9 3.33.2 3.72.3 86.381.1
+s.d. 4.1 5.8 10.713.3 0.40.3 1.2 3.0 0.5 0.6 1.61.1 2.51.1 12.314.9
+2* 10.816.7 67.068.3 0.00.0 0.6 0.4 0 0 1.99.3 4.61.0 84.995.5
+C-6-G:codeine-6-glucuronide;M-3-G:morphine-3-glucuronide;M-6-G:morphine-6-glucuronide;N-C:norcodeineconjugates;S:single
+dose;C:chronicdosing.
+*:poormetaboliser.
+Table5 Intrinsicclearanceandpartialclearancesofcodeinetoitsmeasurablemetabolitesaftersingleand
+chroniccodeineadministration
+Partialclearance(mlmin-) Intrinsicclearance
+Morphine Norcodeine Codeine-6-glucuronide(mlmin-')
+Subject singlechronic singlechronic singlechronic single chronic
+1 154 70 166 55 940 1153 1610 1604
+3 97 103 124 91 995 1128 1557 1616
+4 141 128 91 58 709 606 1759 1366
+5 148 65 91 88 946 773 1484 1616
+6 145 177 105 123 1040 758 1570 1501
+7 93 98 77 74 1010 607 1434 1134
+8 180 190 68 42 756 495 1562 1391
+Mean 137 119 103 76 914 789 1568 1461
+s.d. 31 49 33 27 129 258 103 178
+2* 8 5 90 117 971 825 1450 1205
+*:poormetaboliser.
+othersubjectsafterbothregimens(Table5).Thepartial
+clearancetonorcodeinewasnotsignificantlydifferent
+thanthattomorphine(n=7).Thepartialclearanceto
+codeine-6-glucuronideshowedtheleastdegreeofvari-
+ationbetweensubjects.Therewasnosignificantdiffer-
+enceintheintrinsicclearanceofcodeinebetweensingle
+andchronicdoses.
+Therewerenoadverseeffectsofcodeineinanyofthe
+subjectsduringthestudies.
+Discussion
+Thevaluesofthepharmacokineticparametersfor
+codeineafterasingledosearesimilartothosereported
+previously(Findlayetal.,1977,1978,1986;Quidinget
+al.,1986;Rogersetal.,1982).Theplasmaelimination
+half-lifefoundbyGuayandcoworkers(1987)of4.5-5.6
+hissomewhatlongerthanthosefoundbyusandothers.
+Thisdifferencemayhaveresultedfromthenonspecific
+r.i.a.usedinGuay'sstudy.Thepharmacokineticsof
+codeineaftermultipledoseshavebeenreportedpre-
+viously(Guayetal.,1987;Quidingetal.,1986).In
+contrasttotheresultsofGuayandcoworkers(1987),the
+maximumplasmaconcentrationofcodeineinthisstudy
+increasedsignificantlyaftermultipledosingcomparedto
+thesingledoseandthisisinagreementwiththefindings
+ofQuidingandcoworkers(1986).Thiscanbeexplained
+bythepresenceofresidualcodeineinplasmafrom
+previousdoses.Steady-statehadbeenachievedsince
+thezeroand8hplasmacodeineconcentrationswerenot
+significantlydifferent.Exceptfortheincreaseinmaxi-
+mumconcentrationafterchronicdosing,itwouldappear
+thattheabsorptionanddispositionofcodeinearenot
+alteredbychronicadministration,atleastintheshort
+termandatthedosesstudied.
+Thesalivatoplasmacodeineconcentrationratiowas
+greaterthanunity,confirmingthereportbyLeeand
+coworkers(1986).Severalpropertiesofcodeinewould
+promoteitspenetrationandretentioninsaliva.Codeine
+isabasiccompoundwithahighpKa(8.2)andlow(7-25%)plasmaproteinbinding(Moffatetal.,1986).Itis
+alsohighlylipophilic(octanol/waterpartitioncoefficient
+3.98;Moffatetal.,1986).Theinversecorrelation
+betweensalivapHandsalivacodeineAUCisinkeeping
+withthetheoreticalpredictionbasedontheHenderson-
+Hasselbalchequation.Pholcodine,adrugwithsimilar
+physicochemicalpropertiestocodeine,alsohasahigh
+388 Z.R.Chenetal.
+salivatoplasmaconcentrationratio(Chenetal.,1988b).
+ThefindingthatthesalivacodeineAUC duringthe
+dosingintervalatsteadystatewashigherthanthatafter
+thesingledosemaybeduetothedifference(P=0.05)
+insalivapHbetweenthetwotreatments,whichaveraged
+6.6and6.4afterthesingleandchronicdose,respectively.
+Codeine-6-glucuronidewasnotdetectedinsaliva,a
+likelyresultofitshighpolarityandpoorlipophilicity.
+Therenalclearanceofcodeinerangedfrom67to265
+mlmin-'.Sincethedegreeofplasmabindingissmall(7-
+25%;Moffatetal.,1986),andasthesubjects'creatinine
+clearancesrangedfrom90to132mlmin-',thesedata
+indicatethatinadditiontoglomerularfiltration,codeine
+appearstoundergoactivesecretionintothelumenofthe
+proximaltubule.Thesignificantnegativecorrelation
+betweenrenalclearanceandurinepHsuggeststhat
+passivereabsorptioninthedistaltubule/collectingduct
+alsooccurredassuggestedbytheobservationsof
+Vaughan&Beckett(1973).
+Wehaveconfirmedtheresultsofothers(Adleretal.,
+1955;Nomofetal.,1977;Oberst,1941;Yueetal.,
+1989a,b)thatcodeine-6-glucuronideisthemajormeta-
+boliteofcodeineinman.However,toourknowledge,
+oursisthefirststudytodirectlydeterminecodeine-6-
+glucuronidedispositionaftercodeineadministrationin
+humans.Thepharmacokineticsofcodeineglucuronide
+haveonlybeenstudiedindirectlybyGuayandcoworkers
+(1987,1988)using,B-glucuronidasehydrolysisandr.i.a.
+Intheirstudy,concentrationsoftheglucuronidewere
+correctedtoreflecttheintrinsicallylessthancomplete
+efficiencyofenzymehydrolysis(Guayetal.,1988).In
+addition,theefficiencyofhydrolysiscanbefurther
+reducedinbiologicalmedia(Chenetal.,1989b)because
+ofenzymeinhibitorswhicharenaturallypresentin
+biologicalfluids(Boyland&Williams,1960;Combieet
+al.,1982;Levvy,1952).Themeanapparentplasmahalf-
+lifeofcodeine-6-glucuronideinoursubjectswas3.2h
+whichwasnotsignificantlydifferentfromthatofcodeine,
+reflectingformation-dependentclearanceofthiscon-
+jugate.Therenalclearanceofcodeine-6-glucuronide
+wasmuchlowerthancreatinineclearance.Sincethe
+plasmabindingofcodeine-6-glucuronidewasonly8%,
+therenalclearancebyfiltrationwouldbebetween83
+and121mlmin-'.Insevenoftheeightsubjects,the
+renalclearanceofcodeine-6-glucuronidewassubstan-
+tiallylowerthanthesevalues,suggestingthatitwas
+filteredandreabsorbed.However,othermechanisms
+needtobeconsidered.Forexample,hydrolysisof
+codeine-6-glucuronidetocodeineinthekidneyand
+urinarytractcouldresultinaninverserelationship
+betweentheapparentrenalclearancesofthetwosub-
+stances.Nosuchrelationshipwasfound.Giventhehigh
+polarityoftheglucuronide,passivereabsorptionis
+unlikelytooccurandanactivecarrier-mediatedprocess
+shouldbeconsidered.Wehavedemonstratedapparent
+reabsorptionofmorphine-3-and-6-glucuronideinthe
+isolatedperfusedratkidney(Sallustioetal.,1989).The
+mechanismofthisprocessforopioidglucuronides
+remainstobeelucidated.
+Ourfindingswithrespecttotheurinaryrecoveryof
+codeineanditsmajormetabolitesareinaccordwith
+thoseofAdlerandcoworkers(1955),Nomofand
+coworkers(1977),Vaughan&Beckett(1973)andYue
+andcoworkers(1989a,b)
+TheextentofO-demethylationofcodeineshowed
+extremelywideinter-individualvariationconsidering
+therelativehomogeneityofthegroup.Subject2is
+particularlynoteworthysinceonlyasmallamountof
+totalmorphine(about0.5%ofdose)wasrecoveredin
+urineaftersingleandchronicadministrationofcodeine.
+Inthissubject,thepartialclearancetomorphinewas
+aboutonetwentiethoftheaverageoftheotherseven
+subjects.Thissubjectwasapoormetaboliserofdextro-
+methorphan.Thisfindingofaverylowpartialclearance
+tomorphine,togetherwithotherinvivo(Chenetal.,
+1988;Yueetal.,1989b)andinvitrodata(Dayeretal.,
+1988;unpublishedobservations),confirmsthatthe0-
+demethylationofcodeinetomorphineisundergenetic
+scontrol,cosegregatingwiththenowwelldescribed
+debrisoquine/sparteineoxidativepolymorphism
+(Eichelbaumetal.,1979;Mahgoubetal.,1977;Tucker
+etal.,1977).Codeinecannowbeaddedtothelistof
+thosedrugswhoseoxidativemetabolismisunderphar-
+macogeneticcontrol.Whilstthispathwayforcodeineis
+quantitativelyminor,itspotentialimportancecannotbe
+underestimatedsincetheanalgesiceffectofcodeineis
+currentlyacceptedasbeingmediatedbythehepatic
+formationofmorphine(Jaffe&Martin,1985;Sanfilippo,
+1948).Thusitwouldappearthatsomepatients(about5-
+10%oftheCaucasianpopulation)maynotderiveanal-
+gesiafromcodeine.Thishypothesisiscurrentlybeing
+investigated.
+Thedetectionofthepooroxidativemetaboliserinour
+studycameaboutonlybecauseurinarymetabolitesof
+codeinewereassayed.Thedeterminationofthephar-
+macokineticsofcodeineinplasmaalonewouldhave
+missedthisimportantphenomenonasthispoormeta-
+boliserhadplasmacodeineconcentration-timeprofiles
+whichwerenodifferenttothoseoftheotherseven
+subjects.Thisstudyhighlightstheneedtocharacterize
+themetabolismofadruginadditiontoitsdispositionin
+plasma.
+Codeineisadrugofintermediateextraction(Rowland
+& Tozer,1989)andthisistheresultprimarilyofcon-
+jugationatthe-6-position.Thedemethylationclear-
+anceratestomorphineandnorcodeineweresimilarin
+magnitude,andsubstantiallylower(about1/4)thanfor
+6-glucuronidation.Thepartialclearancesdidnotchange
+aftershorttermchronicadministration,thewayinwhich
+codeineisoftenadministeredclinically.Atpresent,
+littleisknownaboutthefactorswhichalterthemeta-
+bolismofcodeineinhumans.Sincethepartialclearance
+tonorcodeinewasnormalinthepoormetaboliser,it
+wouldbereasonabletoinferthatthecontrolofthetwo
+demethylationprocesses(N-demethylationtonorco-
+deine,0-demethylationtomorphine)ismediatedby
+differentcytochromeP-450isoenzymes.Itisimportant
+toidentifythefactorswhichregulatethedemethylations
+andglucuronidationofcodeine.Withregardto0-
+demethylationofcodeine,whichiscatalysedbycyto-
+chromeP-450IID6(Nebertetal.,1989),geneticfactors
+anddrugssuchasquinidine(aspecificinhibitorof
+cytochromeP-450IID6(Brinnetal.,1986))areimport-
+ant.We arenotawareofanyinformationregarding
+factorswhichmayaltertheN-demethylationprocess.
+Severaldrugshavebeenshowntoinhibittheglucu-
+ronidationofcodeineinhumanlivermicrosomes(Yue
+etal.,1990).Anyfactorwhichmightaltertheglucu-
+Dispositionandmetabolismofcodeine389
+ronidationofcodeineandthusaltertheproportionof
+theclearanceofcodeinetomorphinecouldhaveimport-
+antclinicalimplications.
+Glucuronidationisgenerallyregardedasadetoxifica-
+tionmechanismforxenobiotics.However,morphine-6-
+glucuronidehasbeendocumentedtobeapharmaco-
+logicallyactivecompoundanditsanalgesicpotencyis
+equaltoorhigherthanthatofmorphine(Osborneetal.,
+1988;Pasternaketal.,1987;Yoshimuraetal.,1973).
+Whethercodeine-6-glucuronidehaspharmacological
+activityisunknown.Thebindingaffinityofcodeine-6-
+glucuronidetothe,u-opioidreceptorinratbrainhomo-
+genateis300timeslessthanthatofmorphineand
+morphine-6-glucuronide,butsimilartothatofcodeine
+(Irvineetal.,1989).Plasmaconcentrationsofcodeine-6-
+glucuronidewere15timeshigherthancodeineand
+couldbesufficienttocontributetoanalgesiaand/or
+toxicity.
+Thereareseveralpotentiallyimportantclinicalimpli-
+cationsofourfindings.Inhealthyyoungsubjects,there
+isunlikelytobeunpredictableaccumulationofcodeine
+andcodeine-6-glucuronidewithchronicadministration.
+Thismaynotbethecase,however,inpatientswith
+impairedrenalfunctionandintheelderly,inwhom
+plasmacodeine-6-glucuronideconcentrationsmaybe
+substantialandcouldcontributetoadverseeffects.Poor
+metabolisersofcodeinemaynotderiveanyofthe
+pharmacologicaleffectsassociatedwithcodeine.
+DrChenwassupportedbytheNationalHealthandMedical
+ResearchCouncilofAustraliaandisnowaFloreyResearch
+FellowoftheRoyalAdelaideHospital.DrSomogyiwas
+supportedbytheRoyalAdelaideHospitalResearchFund.
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+(Received22May1990,
+accepted19October1990)

papers/PKDB00094.md

@@ -0,0 +1,21 @@
+# Plasma and oral fluid pharmacokinetics and pharmacodynamics after oral codeine administration.
+
+Insook Kim, Allan J Barnes, Jonathan M Oyler, Raf Schepers, Robert E Joseph, Edward J Cone, Diana Lafko, Eric T Moolchan, Marilyn A Huestis
+
+*Clinical chemistry* (2002)
+
+PMID: 12194925
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+**BACKGROUND:** The ease, noninvasiveness, and safety of oral fluid collection have increased the use of this alternative matrix for drugs-of-abuse testing; however, few controlled drug administration data are available to aid in the interpretation of oral fluid results.
+
+**METHODS:** Single oral codeine doses (60 and 120 mg/70 kg) were administered to 19 volunteers. Oral fluid and plasma were analyzed for free codeine, norcodeine, morphine, and normorphine by solid-phase extraction combined with gas chromatography-mass spectrometry (SPE/GC-MS). Physiologic and subjective effects were examined.
+
+**RESULTS:** Mean (SE) peak codeine concentrations were 214.2 +/- 27.6 and 474.3 +/- 77.0 micro g/L in plasma and 638.4 +/- 64.4 and 1599.3 +/- 241.0 micro g/L in oral fluid. The oral fluid-to-plasma ratio for codeine was relatively constant ( approximately 4) from 1 to 12 h. The mean half-life (t(1/2)) of codeine was 2.2 +/- 0.10 h in plasma and 2.2 +/- 0.16 h in oral fluid. Significant dose-related miosis and increases in sedation, psychotomimetic effect, and "high" occurred after the high dose. Mean codeine oral fluid detection time was 21 h with a 2.5 microg/L cutoff, longer than that of plasma (12-16 h). Detection times with the proposed Substance Abuse and Mental Health Services Administration cutoff (40 microg/L) were only 7 h. Norcodeine, but not morphine or normorphine, was quantified in both plasma and oral fluid.
+
+**CONCLUSIONS:** The disposition of codeine over time was similar in plasma and oral fluid, but because of high variability, oral fluid codeine concentrations did not reliably predict concurrent plasma concentrations. Oral fluid testing is a useful alternative matrix for monitoring codeine exposure with a detection window of 7-21 h for single doses, depending on cutoff concentrations. These controlled drug administration data should aid in the interpretation of oral fluid codeine results.

papers/PKDB00094.pdf

@@ -0,0 +1,3 @@
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+oid sha256:ce20fedf6b463edfb7da0770e207d2dbcf7d651b113dd705ef11cb1f7d7fe617
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papers/PKDB00094.txt

@@ -0,0 +1,1011 @@
+Plasma and Oral Fluid Pharmacokinetics and
+Pharmacodynamics after Oral Codeine
+Administration
+Insook Kim,1 Allan J. Barnes, 1 Jonathan M. Oyler, 1 Raf Schepers,1
+Robert E. Joseph, Jr., 2 Edward J. Cone, 3 Diana Lafko,1 Eric T. Moolchan, 1 and
+Marilyn A. Huestis 1*
+Background: The ease, noninvasiveness, and safety of
+oral fluid collection have increased the use of this
+alternative matrix for drugs-of-abuse testing; however,
+few controlled drug administration data are available to
+aid in the interpretation of oral fluid results.
+Methods: Single oral codeine doses (60 and 120 mg/70
+kg) were administered to 19 volunteers. Oral fluid and
+plasma were analyzed for free codeine, norcodeine,
+morphine, and normorphine by solid-phase extraction
+combined with gas chromatography–mass spectrometry
+(SPE/GC-MS). Physiologic and subjective effects were
+examined.
+Results: Mean (SE) peak codeine concentrations were
+214.2 /H1155027.6 and 474.3 /H1155077.0
+/H9262g/L in plasma and 638.4 /H11550
+64.4 and 1599.3 /H11550241.0 /H9262g/L in oral fluid. The oral
+fluid-to-plasma ratio for codeine was relatively constant
+(/H110114) from 1 to 12 h. The mean half-life ( t
+1/2) of codeine
+was 2.2 /H115500.10 h in plasma and 2.2 /H115500.16 h in oral fluid.
+Significant dose-related miosis and increases in seda-
+tion, psychotomimetic effect, and “high” occurred after
+the high dose. Mean codeine oral fluid detection time
+was 21 h with a 2.5
+/H9262g/L cutoff, longer than that of
+plasma (12–16 h). Detection times with the proposed
+Substance Abuse and Mental Health Services Adminis-
+tration cutoff (40
+/H9262g/L) were only 7 h. Norcodeine, but
+not morphine or normorphine, was quantified in both
+plasma and oral fluid.
+Conclusions: The disposition of codeine over time was
+similar in plasma and oral fluid, but because of high
+variability, oral fluid codeine concentrations did not
+reliably predict concurrent plasma concentrations. Oral
+fluid testing is a useful alternative matrix for monitor-
+ing codeine exposure with a detection window of 7–21 h
+for single doses, depending on cutoff concentrations.
+These controlled drug administration data should aid in
+the interpretation of oral fluid codeine results.
+© 2002 American Association for Clinical Chemistry
+Traditional matrices for drugs-of-abuse testing are urine
+and plasma, but interest in oral fluid monitoring has
+increased because of the ease and noninvasiveness of
+specimen collection. Disadvantages of urine testing in-
+clude concentration variations attributable to changing
+fluid intake and a greater possibility for adulteration or
+substitution. Oral fluid collection can be readily observed
+without loss of privacy, reducing or eliminating the risk of
+an invalid specimen. Although plasma specimens provide
+an estimate of the actual circulating concentrations of
+analytes, blood collection is invasive, causes discomfort,
+and exposes the individual to the risk of infection. Mon-
+itoring of oral fluid maybe especially advantageous and
+important when multiple serial samples are needed or
+when drug concentrations in children are required.
+Earlier studies demonstrated that many therapeutic
+drugs are transferred rapidly from plasma to saliva by
+drug transport across biological membranes ( 1 –6). Drug
+entry into oral fluid is dependent on the physicochemical
+characteristics of the drug molecule (lipid solubility, de-
+gree of ionization, molecular size) and the membrane. It is
+generally presumed that the drug concentration in oral
+fluid corresponds to the concentration of free or unbound
+drug in the plasma, the physiologically active drug com-
+ponent. Lipid-soluble basic drugs that are not extensively
+bound to plasma proteins preferentially partition into oral
+1 Chemistry and Drug Metabolism, Intramural Research Program, Na-
+tional Institute on Drug Abuse, NIH, 5500 Nathan Shock Dr., Baltimore, MD
+21224.
+2 Clinical Affairs, Amgen Inc., 1 Amgen Center Dr., Thousand Oaks, CA
+91320-1799.
+3 ConeChem Research, 441 Fairtree Dr., Severna Park, MD 21146.
+*Author for correspondence. Fax 410-550-2971; e-mail mhuestis@intra.
+nida.nih.gov.
+Received March 18, 2002; accepted May 9, 2002.
+Clinical Chemistry 48:9
+1486 –1496 (2002) Drug Monitoring and
+Toxicology
+1486
+fluid. In addition, oral fluid (pH 6.5–7.2) is generally more
+acidic than plasma; consequently, basic drugs will parti-
+tion in oral fluid at higher concentrations than in plasma
+(7, 8).
+Oral fluid testing has been used for therapeutic drug
+monitoring of phenytoin, antipyrine, primidone, ethosux-
+imide, and theophylline concentrations (9–14 ). Oral fluid
+testing has also been developed for drugs of abuse,
+including amphetamines, barbiturates, cannabinoids, co-
+caine, diazepam, lysergic acid diethylamide, opioids, and
+phencyclidine (15–17 ). Therefore, oral fluid may be a
+viable alternative testing matrix to plasma for drug treat-
+ment, workplace drug testing, child custody cases, driv-
+ing under the influence, and criminal investigations.
+Nonstimulated oral fluid samples can be collected by
+expectoration or draining oral fluid into a tube. Stimu-
+lated oral fluid samples have been conventionally ob-
+tained by chewing Parafilm wax or Teflon or through
+exposure of the oral cavity to citric acid candy or crystals.
+In addition, several oral fluid collection devices and
+techniques, such as Salivette
+®, OraSure ®, and the Oral-
+Diffusion-Sink device, have been developed to facilitate
+and standardize oral fluid sampling. The advantages and
+disadvantages of several of these new devices that utilize
+absorbent cotton swabs, rolls, or salt solutions to collect
+oral fluid have been reviewed recently (18, 19 ).
+Codeine is an opiate commonly prescribed for pain
+relief and for cough suppression. Although widely used
+for therapy, codeine is also abused for its euphoric and
+depressant effects and to prevent opiate withdrawal (20–
+23 ). Because of increasing abuse and potential perfor-
+mance-impairing effects, codeine is included in workplace
+and military drug testing programs. Recently, the Sub-
+stance Abuse and Mental Health Services Administration
+(SAMHSA)
+4 suggested a 40 /H9262g/L screening and confir-
+mation cutoff concentration for federally mandated test-
+ing for codeine in oral fluid.
+Although several studies have addressed the disposi-
+tion of codeine in plasma and oral fluid after single or
+multiple doses (7, 24–28 ), there remain many questions
+on codeine oral fluid pharmacokinetics and on the corre-
+lation of drug concentration to concurrent physiologic
+and behavioral effects. This controlled clinical drug ad-
+ministration study evaluates these relationships and de-
+termines the sensitivity and detection time of codeine in
+oral fluid.
+Materials and Methods
+human participants
+Twelve male and 7 female healthy volunteers participated
+in the controlled drug administration protocol. Of the 19
+participants, 14 were African American, 3 were Cauca-
+sian, and 2 were Hispanic. Their mean (SE) age was 34.8/H11006
+1.1 years (range, 23–43 years) with a mean (SE) weight of
+78.0 /H110063.4 kg (range, 56.6 –106.5 kg). The protocol was
+approved by the National Institute on Drug Abuse Insti-
+tutional Review Board. Participants provided written
+informed consent and were paid for their participation.
+Screening procedures included a comprehensive physical
+and psychologic examination. Participants reported a
+history of cocaine and opioid use, verified by a positive
+urine test before admission, and were not physically
+dependent on drugs or medications, with the possible
+exception of nicotine and caffeine. During the 10-week
+study, all participants resided on the closed research unit
+of the Intramural Research Program, National Institute on
+Drug Abuse.
+drug administration
+Codeine sulfate for oral human administration was ob-
+tained from Roxane Laboratories and was prepared in
+polished lactose capsules (Amend Drug and Chemical
+Co.). Participants were admitted to the research unit 20
+days before the first scheduled dose to permit previously
+self-administered drugs to be cleared from the body.
+Three low doses (60 mg/70 kg) and three high doses (120
+mg/70 kg) of codeine sulfate were taken within 7 days
+(minimum separation of 48 h) in weeks 4 and 8, respec-
+tively.
+plasma and oral fluid specimens
+Whole-blood samples were withdrawn with a syringe
+through an indwelling catheter in the antecubital vein and
+collected in Vacutainer Tubes containing sodium fluoride
+and acetic acid. Standard green top (sodium lithium)
+Vacutainer Tubes were supplemented with 25
+/H9262Lo f
+saturated sodium fluoride and 25 /H9262L of 100 g/L acetic
+acid per milliliter of blood to improve the stability of
+cocaine in blood. These specimens were analyzed for
+cocaine and metabolites in addition to the opiate analytes
+required for this study. Specimens were placed on ice and
+centrifuged (2060 g for 10 min) to separate the plasma.
+Plasma was transferred to polypropylene cryotubes and
+frozen at /H1100220 °C until analysis. Specimens were collected
+at the following times: predose, 0.08, 0.17, 0.25, 0.50, 1, 2,
+4, 8, 12, 24, and 48 h after the first drug administration.
+Citric acid candy-stimulated oral fluid specimens were
+obtained at the same time points after the first codeine
+dose. Oral fluid was also collected with citric acid candy
+stimulation at the same time points after the second and
+third doses in four participants to study intrasubject
+variability (group I). In a second group of four partici-
+pants (group II), three oral fluid collection methods were
+used to study drug concentrations with different collec-
+4 Nonstandard abbreviations: SAMHSA, Substance Abuse and Mental
+Health Services Administration; BSTFA, N,O-bis(trimethyl)trifluoroacetamide;
+TMCS, trimethylchlorosilane; MTBSTFA, N-methyl-N-(tert-butyldimethylsilyl)-
+trifluoroacetamide; TBDMCS, tert-butyldimethylchlorosilane; SPE, solid-phase
+extraction; GC-MS, gas chromatography –mass spectrometry; LOD, limit of
+detection; LOQ, limit of quantification; S/P, oral fluid/plasma; cmax, peak
+concentration; tmax, time of peak concentration; t1/2, half-life; AUC, area under
+the curve; ARCI, Addiction Research Center Inventory; SDQ, Single Dose
+Questionnaire; VAS, Visual Analog Scales; PCAG, Phenobarbital-Chlorprom-
+azine-Alcohol group; and LSD, lysergic acid diethylamide.
+Clinical Chemistry 48, No. 9, 2002 1487
+tion methods. Oral fluid was collected with citric acid
+candy stimulation after the first dose, with the Salivette
+citric acid-treated cotton swab after the second dose, and
+with the Salivette neutral cotton swab after the third dose.
+Specimens collected with the Salivette devices were cen-
+trifuged in conical tubes to release oral fluid from the
+cotton. Subsequently, oral fluid was transferred to
+polypropylene cryotubes and frozen at /H1100220 °C until anal-
+ysis.
+chemicals and reagents
+Chemicals were obtained from the following sources:
+codeine /H18528PO
+4,[ 2H3]codeine hydrochloride /H185282H 2O,
+norcodeine hydrochloride /H185283H 2O, morphine sulfate,
+[2H3]morphine hydrochloride /H185283H 2O, and normorphine
+hydrochloride /H18528H2O were from Sigma Chemicals; N,O-
+bis(trimethyl)trifluoroacetamide (BSTFA) containing 1%
+trimethylchlorosilane (TMCS) and N-methyl-N-(tert-bu-
+tyldimethylsilyl)trifluoroacetamide (MTBSTFA) with 1%
+tert-butyldimethylchlorosilane (TBDMCS) were from
+Pierce Chemical. Deuterated codeine was used as the
+internal standard for codeine and norcodeine, and deu-
+terated morphine was used as the internal standard for
+morphine and normorphine. Solid-phase extraction (SPE)
+columns (Clean Screen ZSDAU020) and filtration col-
+umns (RFV02F4P) were obtained from United Chemical
+Technologies. Solvents were HPLC grade and purchased
+from the following sources: methylene chloride, 2-propa-
+nol, and acetonitrile were from Mallinckrodt Baker Inc.;
+and methanol was from Fisher Scientific. Sodium acetate,
+acetic acid, ammonium hydroxide, and hydrochloric acid
+were A.C.S. reagent grade and were obtained from
+Mallinckrodt Baker.
+analytical procedure
+Calibrators and quality-control, oral fluid, and plasma
+samples were analyzed for codeine, norcodeine, mor-
+phine, and normorphine by SPE and gas chromatog-
+raphy–mass spectrometry (GC-MS) according to a previ-
+ously published procedure (29 ). Calibrators were
+prepared at drug concentrations from 1.25 to 1000
+/H9262g/L
+in drug-free oral fluid or plasma for codeine and its
+metabolites. Drug-free oral fluid was collected from
+healthy volunteers, and drug-free plasma was purchased
+from Red Cross Blood Services. We verified these matrices
+to be drug free [below the limit of detection (LOD) of the
+method] before preparation of calibrators and controls.
+Drug-free oral fluid and plasma were enriched with
+different stock solutions of codeine, norcodeine, mor-
+phine, and normorphine at 0, 12.5, 25, and 250
+/H9262g/L to
+prepare quality-control samples. Briefly, for the extrac-
+tion, 1 mL of calibrator, control, and clinical samples was
+mixed with 2 mL of sodium acetate buffer (2 mol/L, pH
+4). [
+2H3]Codeine and [2H3]morphine were added as inter-
+nal standards (100 /H9262L of a 1 mg/L solution) to each
+sample. The SPE columns were preconditioned in the
+following order: 1 mL of methylene chloride–2-propanal–
+concentrated ammonium hydroxide (80:20:2 by volume),
+3 mL of methanol, twice with 3 mL of deionized water,
+and 1.5 mL of 2 mol/L sodium acetate buffer (pH 4). After
+centrifugation of samples, the supernatant was decanted
+onto preconditioned SPE cartridges and washed with 2
+mL of deionized water, 1.5 mL of 0.2 mol/L hydrochloric
+acid, and twice with 1 mL of methanol. Analytes were
+eluted four times with 1 mL of methylene chloride –2-
+propanol–concentrated ammonium hydroxide (80:20:2 by
+volume), and eluates were combined. After the addition
+of 20
+/H9262L of MTBSTFA /H110011% TBDMCS, eluates were
+evaporated to dryness under nitrogen, reconstituted with
+20
+/H9262L of acetonitrile, and transferred to autosampler vials
+for dual derivatization. After the addition of 20 /H9262Lo f
+MTBSTFA /H110011% TBDMCS, vials were loosely capped and
+placed in a heat block at 80 °C for 15–20 min. BSTFA /H110011%
+TMCS (20 /H9262L) was added to each vial, and extracts were
+crimp-capped and heated at 80 °C for 45 min. A dual
+derivatization procedure was used because the trimethyl-
+silyl derivatives of morphine and norcodeine have com-
+mon mass fragments and partially coelute when nonpolar
+GC phases are used for separation with single-step tri-
+methylsilane derivatization. The derivatized extract (1
+/H9262L)
+was injected onto the GC-MS system in the electron
+impact mode. Specimens were analyzed with the low
+(2.5–50
+/H9262g/L) or high calibration curve (50 –500 /H9262g/L).
+Split curves were required to obtain adequate sensitivity
+and linearity ( r /H113500.98) for the four analytes.
+GC-MS analysis was performed on a Hewlett-Packard
+5890A gas chromatograph interfaced with a Hewlett-
+Packard 5972 mass-selective detector or a Hewlett-Pack-
+ard 6890 gas chromatograph interfaced with a Hewlett-
+Packard 5973 mass-selective detector. The instruments
+were operated in the splitless mode. Separation of ana-
+lytes was achieved with a HP-1 [12 m /H110030.2 mm (i.d.);
+0.33-
+/H9262m film thickness] or Phenomenex ZB1 fused-silica
+capillary column [15 m /H110030.2 mm (i.d.); 0.25- /H9262m film
+thickness] with helium as carrier gas at a flow rate of 1.0
+mL/min. The initial column temperature of 70 °C was
+held for 1.5 min, followed by increases to 175 °Ca t
+30 °C/min, to 250 °Ca t2 3 °C/min, and to 325 °Ca t
+18 °C/min with a 1.0-min final hold time. The mass
+spectrometer was operated in the electron impact mode
+with a dwell time of 10 ms/ion. Three ions for each
+analyte were monitored. The ions for each compound
+were (quantitative ion indicated in parentheses):
+[
+2H3]codeine, m/z (374), 237, 181; codeine, m/z (371), 234,
+178; norcodeine, m/z (429), 254, 292; [ 2H3]morphine, m/z
+(417), 474, 281; morphine, m/z (414), 471, 278; and normor-
+phine, m/z (472), 529, 350. Ion ratios of quality-control
+samples and participant samples were required to be
+within /H1100620% of those observed for the 10- and 100-ng
+calibrators for the low and high calibration curves, respec-
+tively. The upper limit of linearity for the high calibration
+curve was 500
+/H9262g/L; specimens that exceeded 500 /H9262g/L
+were diluted with blank oral fluid or plasma and reex-
+tracted and analyzed.
+1488 Kim et al.: Codeine Plasma and Oral Fluid Pharmacokinetics
+The LOD of the method was defined as the lowest
+concentration at which signal-to-noise ratios of the iden-
+tifying ions (determined by peak height) were /H110223:1,
+chromatography and retention time were acceptable, and
+three of four replicates at specified concentrations had ion
+ratios within /H1100620% of those observed for the 10-ng
+calibrator. The limit of quantification (LOQ) was the
+lowest concentration that met LOD criteria plus the re-
+quirement that three of four replicates quantify within /H11006
+20% of the target concentration. The LOD and LOQ of the
+method were 2.5
+/H9262g/L for all analytes. Interassay preci-
+sion and accuracy data for codeine and its metabolites
+were determined for three concentrations (12.5, 25, and
+250
+/H9262g/L) in plasma and oral fluid. The interassay CVs
+for plasma (n /H1100510 runs; 2 –3 replicates per run) were as
+follows: codeine, 13%, 13%, and 7.8%, respectively; nor-
+codeine 13%, 13%, and 13%; morphine 13%, 8.7%, and
+13%; normorphine 8.0%, 13%, and 15%. Interassay CVs
+were as follows for oral fluid: codeine, 8.7%, 7.0%, and
+5.1%; norcodeine, 23%, 30%, and 10%; morphine, 11%,
+7.7%, and 16%; and normorphine, 29%, 25%, and 18%.
+oral fluid:plasma (s/p) and norcodeine:codeine
+(ncod:cod) ratios
+The S/P ratio was calculated by dividing the oral fluid
+drug concentration by the plasma drug concentration for
+specimens collected at the same time after codeine admin-
+istration. NCOD:COD ratios were obtained by dividing
+norcodeine by codeine concentrations and multiplying by
+100.
+pharmacokinetic analysis
+Peak plasma and oral fluid concentrations ( cmax) and the
+time of peak concentration ( tmax) were obtained directly
+from the concentration –time data. Elimination half-lives
+(t1/2) were calculated as t1/2 /H11005ln2//H9261, where the elimina-
+tion rate constant (/H9261) was calculated from the slope of the
+terminal portion of the semilogarithmic concentration –
+time curve by linear regression analysis. The areas under
+the plasma or oral fluid concentration –time curves
+(AUCs) were calculated by the linear trapezoidal rule for
+24 h after drug administration. Plasma and oral fluid
+pharmacokinetic parameters were derived by noncom-
+partmental methods with the use of WinNonlin Profes-
+sional software (Ver. 3.2; Pharsight Co.). Uniform weight-
+ing for all data points was used throughout the analysis.
+data analysis
+Data are represented as mean /H11006SE. Statistical analysis
+was performed by SPSS software (Ver. 10.0; SPSS Inc.).
+For plasma and oral fluid drug concentrations, multivar-
+iate ANOVA was used for statistical analysis of the data.
+For physiologic and subjective effect data, repeated-mea-
+sures ANOVA was used. Factors were dose (60 and 120
+mg/70 kg of codeine) and time (hours after drug admin-
+istration). Statistical significance was assumed when P
+was /H113490.05. Separate paired t-tests or post hoc t-tests were
+performed between placebo and effects at each codeine
+dose when dose and dose /H11003time effects were significant.
+physiologic and behavioral measurements
+Participants underwent physiologic measurements before
+and 0.08, 0.17, 0.25, 0.5, 1, 2, 4, 8, and 12 h after placebo
+and oral codeine administration. Physiologic measure-
+ments included pupil size, systolic and diastolic blood
+pressure, pulse, skin temperature, respiration, blood oxy-
+genation, and core temperature. Each participant also
+completed self-rating subjective scales before and 0.08,
+0.17, 0.25, 0.5, 1, 2, 4, an d 8 h after dosing. The Addiction
+Research Center Inventory (ARCI) (30 ), Single Dose
+Questionnaire (SDQ) (31 ), and Visual Analog Scales
+(VAS) were used to assess subjective effects. ARCI self-
+rating subjective subscales consisted of the Morphine-
+Benzedrine group, Phenobarbital-Chlorpromazine-Alco-
+hol group (PCAG), and Lysergic Acid Diethylamide
+(LSD) and the Opiate Withdrawal Subscale. The SDQ,
+modified to provide only subject ratings, consisted of 14
+items that were rated on a scale from 0 (no) to 1 (yes)
+including “feel drug”, “normal”, “skin itchy”, “relaxed”,
+“coasting”, “nodding”, “high”, “sleepy”, “drunken”,
+“nervous”, “drive”, “soap box”, “turning stomach”, and
+“pleasant sick”. VAS assessed the following effects: “stim-
+ulated”, “high”, “anxious”, “sedated”, “down”, and
+“hungry”. Participants marked a line on a scale ranging
+from 0 mm (not at all) to 100 mm (extremely) to indicate
+how they felt at that moment.
+Results
+codeine and metabolite concentrations in
+plasma
+Codeine was the primary analyte detected in plasma.
+Mean codeine plasma concentrations-vs-time curves (n /H11005
+16 for low dose; n /H1100514 for high dose) are illustrated in
+Fig. 1A. All specimens collected before drug administra-
+tion were negative for codeine and metabolites. Plasma
+data were not available for 3 of the 19 participants because
+of phlebotomy problems. Codeine was initially detected
+between 0.17 and 1 h, with a mean of 0.5 /H110060.07 h for the
+low dose and 0.4 /H110060.04 h for the high dose. Plasma
+codeine concentrations peaked between 0.5 an d4ha ta
+mean of 1.3 /H110060.22 h and 1.2 /H110060.18 h for the low and high
+doses, respectively. The mean plasma codeine c
+max was
+214.2 /H1100627.6 /H9262g/L (range, 66.1 –413.2) after the low dose
+and 474.3 /H1100677.0 /H9262g/L (range, 184.0–1158.1) after the high
+dose. Plasma codeine concentration was significantly re-
+lated to dose from 0.5 t o8h( P /H110210.05). The mean
+pharmacokinetic parameters for codeine are shown in
+Table 1. The mean t
+1/2 of codeine in plasma (n /H1100514) was
+2.1 /H110060.08 h (range, 1.5 –2.7 h), and 2.4 /H110060.18 h (range,
+1.4–3.5 h) for low and high doses, respectively. The AUCs
+for codeine were 734 /H1100666 and 1800 /H11006222 h /H18528/H9262g/L for the
+60 and 120 mg/70 kg doses, respectively, also demon-
+strating a significant dose –concentration relationship
+(P /H110050.001).
+Clinical Chemistry 48, No. 9, 2002 1489
+Morphine and normorphine were not detected in any
+specimen based on the method LOQ of 2.5 /H9262g/L; how-
+ever, norcodeine was detected in the plasma after all drug
+doses except for one participant after the low codeine
+dose. Mean norcodeine plasma concentrations vs time
+after oral administration of 60 and 120 mg/70 kg codeine
+sulfate are illustrated in Fig. 1B. Norcodeine was initially
+detected from 0.17 and 2 h after codeine administration at
+a mean of 0.7 /H110060.14 h for the low dose and 0.6 /H110060.08 h
+for the high dose, slightly later than initial detection of the
+parent drug. Plasma norcodeine concentrations peaked
+between 0.5 and 4 h, with a mean peak time of 1.4/H110060.26 h
+after the low dose and 1.5/H110060.17 h after the high dose. The
+mean c
+max for norcodeine was 12.2 /H110061.5 /H9262g/L (range,
+4.2–26.1) and 33.4 /H110064.2 /H9262g/L (range, 9.2 –63.0) for low
+and high doses, respectively. There was a significant
+nonlinear dose–concentration relationship for mean nor-
+codeine in plasma between 0.5 an d8h( P /H110210.05). The
+mean pharmacokinetic parameters for norcodeine in
+plasma and oral fluid are shown in Table 1. The mean t
+1/2
+for norcodeine in plasma was 4.3 /H110060.61 h (range, 2.0 –8.6
+h) for the low dose and 4.3 /H110060.45 h (range, 2.7–6.9 h) for
+the high dose; two to three times longer than that of
+codeine. The mean AUCs for norcodeine in plasma were
+84 /H1100616 and 232 /H1100634 h /H18528/H9262g/L for the low and high doses,
+respectively, and a significant dose –AUC relationship in
+plasma was observed ( P /H110210.001). NCOD:COD ratios
+increased over time during elimination (Fig. 2), indicating
+a longer t
+1/2 for the metabolite compared with the parent
+drug. NCOD:COD ratios ranged from 2% to 46% between
+0.5 and 8 h after codeine ingestion.
+codeine and metabolites in oral fluid
+The time course of codeine concentration in oral fluid was
+similar to that seen in plasma (Fig. 1A). Generally, codeine
+concentrations were higher in oral fluid than in plasma (P
+/H110210.05 for both doses from 0.5 to 8 h). Codeine was initially
+detected in oral fluid between 0.08 and 1.0 h with a mean
+of 0.5 /H110060.05 h for the low dose and 0.4 /H110060.05 h for the
+high dose, comparable to initial detection in plasma. Oral
+fluid concentrations peaked at 0.5 –4 h with a mean of
+1.7 /H110060.23 h and 1.6 /H110060.14 h with concentrations of
+638.6 /H1100664.4
+/H9262g/L (range, 184.0 –1288.8 /H9262g/L) and
+1599.3 /H11006241.0 /H9262g/L (range, 619.6 –3350.2 /H9262g/L) after the
+60 and 120 mg/70 kg doses, respectively. There were
+significant dose –concentration relationships for codeine
+Fig. 1. Mean concentrations of codeine ( A)
+and norcodeine ( B) in plasma and oral fluid
+after a single dose.
+/H18554, plasma concentration after 60 mg/70 kg dose
+of codeine (n /H1100516 for codeine; n /H1100513 for
+norcodeine); E, plasma concentration after 120
+mg/70 kg dose (n /H1100514 for codeine; n /H1100513 for
+norcodeine); Œ, oral fluid concentration after 60
+mg/70 kg dose (n /H1100519 for codeine; n /H1100517 for
+norcodeine); /H12135, oral fluid concentration after 120
+mg/70 kg dose (n /H1100513 for codeine; n /H1100513 for
+norcodeine). Bars, SE.
+Table 1. Mean pharmacokinetic parameters for codeine and norcodeine in plasma and oral fluid.
+Dose,
+mg/70 kg n cmax,a /H9262g/L tmax,a h t1/2,a h
+AUC24,a,b
+h /H18528/H9262g/L
+Codeine
+Plasma 60 16 214.2 /H1100627.6 1.3 /H110060.22 2.1 /H110060.08 734 /H1100666
+120 14 474.3 /H1100677.0 1.2 /H110060.18 2.4 /H110060.18 1800 /H11006222
+Oral fluid 60 19 638.6 /H1100664.4 1.7 /H110060.23 2.5 /H110060.21 2612 /H11006408
+120 13 1599.3 /H11006241.0 1.6 /H110060.14 1.8 /H110060.19 5827 /H11006766
+S/P ratio 60 14 3.4 /H110060.6
+120 13 4.1 /H110060.8
+Norcodeine
+Plasma 60 13 12.2 /H110061.5 1.4 /H110060.26 4.3 /H110060.61 84 /H1100616
+120 13 33.4 /H110064.2 1.5 /H110060.17 4.3 /H110060.45 232 /H1100634
+Oral fluid 60 17 17.1 /H110063.1 2.1 /H110060.31 7.9 /H110062.17 144 /H1100640
+120 13 46.7 /H1100617.0 2.4 /H110061.19 4.6 /H110061.11 279 /H1100697
+a Data are mean /H11006SE.
+b AUC24, AUC for 24 h.
+1490 Kim et al.: Codeine Plasma and Oral Fluid Pharmacokinetics
+in oral fluid collected from 0.5 t o 4 h after oral adminis-
+tration ( P /H110210.05). The mean t1/2 of codeine in oral fluid
+was 2.5 /H110060.21 h (range, 1.0 –3.8 h) for the low dose and
+1.8 /H110060.19 h (range, 1.2–3.1 h) for the high dose. The AUCs
+for codeine in oral fluid were 2612 /H11006408 and 5827 /H11006766
+h /H18528/H9262g/L for the low and high doses, respectively, dem-
+onstrating a significant dose –AUC relationship for co-
+deine in oral fluid ( P /H110210.001).
+Morphine and normorphine were not detected in oral
+fluid at the LOQ of 2.5 /H9262g/L in any specimen. Norcodeine
+was not detected in oral fluid in 2 of 19 participants after
+the low dose of codeine despite paired plasma sample
+concentrations of 3.9 –12.5
+/H9262g/L. Mean initial detection
+times for norcodeine in oral fluid were 1.0 /H110060.13 h after
+administration of the low dose and 0.8 /H110060.12 h after
+administration of the high dose. The mean norcodeine
+t
+max in oral fluid occurred later than the plasma tmax and
+was 2.1 /H110060.31 and 2.4 /H110060.33 h after administration of the
+low and high doses, respectively. The mean norcodeine
+cmax was 17.1 /H110063.1 /H9262g/L (range, 3.9–58 /H9262g/L) after the 60
+mg/70 kg dose and 46.7 /H1100617.0 /H9262g/L (range, 10.3 –191.2
+/H9262g/L) after the 120 mg/70 kg dose of codeine sulfate. The
+mean disposition profile of norcodeine in oral fluid fol-
+lowed a time course similar to that in plasma (Fig. 1B).
+The mean t
+1/2 of norcodeine in oral fluid was 7.9 /H110062.17 h
+for the low dose (range, 1.6 –30.9 h) and 4.6 /H110061.11 h for
+the high dose (range, 2.1 –9.5 h) and was longer than that
+of codeine. The AUCs for norcodeine in oral fluid were
+144 /H1100640 and 279 /H1100697 h /H18528
+/H9262g/L for the low and high
+doses, respectively. The NCOD:COD ratio in oral fluid
+increased over time, ranging from 0.3% to 31% between
+0.5 and 8 h after administration.
+codeine and norcodeine s/p ratios
+The S/P codeine concentration ratios are illustrated as a
+function of time after drug administration in Fig. 3A.
+Except for early in the time course during codeine absorp-
+tion and distribution, S/P ratios were /H110221. Codeine S/P
+ratios increased up t o 1 h and then were relatively
+constant from 1 to 12 h, with a mean ratio of 4.0 /H110060.5
+(range, 1.1 –17.2) for the low dose and 4.1 /H110060.5 (range,
+0.6–16.4) for the high dose. In addition, the mean codeine
+AUC S/P ratios were 3.4 /H110060.6 (range, 1.3–7.6) for the low
+dose and 4.1 /H110060.8 (range, 1.0 –10.4) for the high dose. As
+shown in Fig. 4, oral fluid codeine concentrations were
+significantly correlated to plasma codeine concentrations
+from 0.5 to 12 h after dosing ( r /H110050.22; P /H110210.0001).
+Higher variability in norcodeine oral fluid concentra-
+tions produced greater variability in norcodeine S/P
+ratios. Mean norcodeine S/P ratios for the low dose (1.7 /H11006
+0.3) tended to be higher than those of the high dose (1.0 /H11006
+0.2; Fig. 3B). Norcodeine S/P ratios were lower than
+concurrent codeine S/P ratios.
+effects of collection method on codeine and
+metabolite oral fluid concentrations
+In group I (n /H110054), citric acid candy was used to stimulate
+oral fluid secretion after administration of three 60 mg/70
+kg doses of codeine (Fig. 5A). Although variability in
+codeine oral fluid concentration was observed, there were
+Fig. 2. Mean NCOD:COD ratios ( /H11003100) in plasma and oral fluid.
+/H18554, plasma concentration after 60 mg/70 kg dose of codeine (n /H1100513); E,
+plasma concentration after 120 mg/70 kg dose (n /H1100513); Œ, oral fluid
+concentration after 60 mg/70 kg dose (n/H1100517); /H12135, oral fluid concentration after
+120 mg/70 kg dose (n /H1100513).
+Fig. 3. Mean S/P ratios for codeine ( A) and
+norcodeine (B) after 60 mg/70 kg dose ( /H18554)
+and 120 mg/70 kg dose ( F) of codeine.
+Bars, SE.
+Clinical Chemistry 48, No. 9, 2002 1491
+no significant differences in the 24-h AUCs of these doses.
+In group II (n /H110054), three different collection methods
+were evaluated: citric acid candy stimulation after the first
+dose, Salivette with citric acid-treated cotton swab after
+the second dose; and Salivette with neutral cotton swab
+after the third dose (Fig. 5B). Codeine concentrations in
+oral fluid collected with citric acid sour candy tended to
+be higher than those in oral fluid collected with the other
+methods up to 2 h after drug administration; however, the
+differences were not statistically significant. After 2 h,
+codeine concentrations in oral fluid were consistent across
+collection methods.
+detection times of codeine in plasma and oral
+fluid
+Detection times for codeine in plasma and oral fluid
+varied by participant, dose, and cutoff concentration.
+Mean detection times for codeine in plasma with a 2.5
+/H9262g/L cutoff were 12.4 /H110061.70 and 16.6 /H110062.57 h for the low
+and high doses, respectively (Table 2). Codeine in oral
+fluid collected with citric acid candy was detectable for
+21.1 /H110061.70 h after the low dose and 21.6 /H110061.38 h after the
+high dose with a 2.5
+/H9262g/L cutoff. Codeine could be
+detected for 5 –9 h longer in oral fluid than in plasma
+when the LOQ cutoff was used. Codeine in oral fluid was
+detected for only7hw i t ha4 0
+/H9262g/L cutoff concentration,
+the suggested SAMHSA confirmatory test cutoff.
+Norcodeine had shorter detection times than codeine
+in both matrices. Mean detection times for norcodeine
+based on the LOQ were 9.4 /H110062.07 and 10.3 /H110061.77 h in
+plasma and 6.0 /H110060.74 and 9.4 /H110061.64 h in oral fluid after
+the low and high doses, respectively.
+physiologic effects
+The effects of 60 and 120 mg/70 kg doses of oral codeine
+on physiologic measures are illustrated in Fig. 6A. Statis-
+tically significant dose-related miosis was observed at 4 h
+after 60 mg/70 kg and from 1 t o 4 h after 120 mg/70 kg
+oral codeine ( P /H110210.05). Pulse, respiration, diastolic and
+systolic blood pressures, skin and core temperatures, and
+blood oxygenation were not significantly affected by
+single 60- or 120-mg doses of oral codeine.
+subjective effects
+Mean responses on the PCAG (sedation) and LSD (psy-
+chotomimetic effect) scales of the ARCI were significantly
+increased compared with placebo ( P /H110210.05) after 120 mg
+of codeine for 1–2 h and 1–4 h, respectively (Fig. 6, B and
+C). In addition, “feel drug ”, “relaxed”, and “high” self-
+rating scales of the SDQ were significantly increased from
+placebo (P /H110210.05) from 0.5 to 2 h after the high dose (Fig.
+6, D –F). No significant differences were found for the
+other ARCI, SDQ, or VAS measures at any time after
+single 60 or 120 mg/70 kg oral codeine doses.
+Discussion
+Oral codeine induced dose-related decreases in pupil size,
+but did not significantly affect other physiologic mea-
+sures. These results are consistent with those of other
+Fig. 5. Oral fluid codeine concentrations.
+(A), mean (n /H110054) oral fluid codeine concentrations
+with citric acid candy stimulation after 60 mg/70 kg
+codeine dose: /H12135, first codeine dose; E, second
+codeine dose; /c141, third codeine dose. ( B), mean
+(n /H110054) oral fluid codeine concentrations after 60
+mg/70 kg codeine dose: f, citric acid candy stim-
+ulation collection method; E, Salivette with citric
+acid-treated cotton swab collection method; Œ,
+Salivette with neutral cotton swab collection
+method. Bars, SE.
+Fig. 4. Correlation of oral fluid to plasma codeine concentration in 19
+participants between 0.5 and 12 h after 60 and 120 mg/70 kg oral
+codeine.
+The regression was calculated by least-squares regression analysis. Equation for
+the line: y /H110051.34x /H11001241.90 (r /H110050.22; P /H110210.0001).
+1492 Kim et al.: Codeine Plasma and Oral Fluid Pharmacokinetics
+studies. Walker and Zacny (32 )found dose-related miosis
+and no effects on other physiologic measures after single
+60- and 120-mg doses of oral codeine. Cone (24 ) reported
+peak miotic effects within 0.75 –1.0 h after 60 and 120 mg
+of intramuscular codeine in one participant.
+In this study, PCAG and LSD scales of the ARCI and
+“feel drug”, “relaxed”, and “high” scales of the SDQ were
+increased after 120 mg/70 kg oral codeine. The PCAG
+scale reflects feelings of sedation and apathy, and the LSD
+scale reflects feelings of dysphoria and sensory and so-
+matic disturbance (30, 33 ). The SDQ relies on participants’
+own personal history of exposure to various drugs. In
+another study (32 ), oral codeine did not affect ARCI
+scores, but produced significant increases in “dry mouth”
+and a trend for increased “skin itch” and “numb” feelings
+after 120 mg of oral codeine. A drug-induced “high” was
+also reported after a 120-mg intramuscular dose of co-
+deine in one participant (24 ).
+Codeine is primarily metabolized by glucuronidation
+to codeine 6-glucuronide, N-demethylation to norcodeine,
+and O-demethylation to morphine in humans (28, 34, 35 ).
+Norcodeine and morphine also undergo glucuronidation.
+In the current study, we analyzed free codeine and free
+metabolites in plasma and oral fluid after single oral
+administration of 60 and 120 mg/70 kg of codeine to
+evaluate the relationship of free codeine and its metabo-
+lites in plasma and oral fluid. Codeine was the primary
+analyte in plasma and oral fluid; the metabolite, norco-
+deine, was also detected in both matrices. Morphine and
+normorphine were not identified in any specimens with a
+2.5
+/H9262g/L LOQ. O ’Neal et al. (25 ) analyzed free codeine
+and free morphine in plasma and oral fluid by GC-MS
+with a 5
+/H9262g/L LOQ after 30 mg of oral liquid codeine.
+Participants (n /H1100517) had previously received three daily
+doses of 30 mg of codeine for 5 days, followed by a 24-h
+washout period. The authors also reported codeine as the
+primary analyte in plasma and oral fluid. Unlike the
+present study, morphine was detected in three saliva
+specimens shortly after dosing with liquid codeine; how-
+ever, concentrations were below the method LOQ. Mor-
+phine was not identified in plasma. Although conjugated
+Table 2. Comparison of codeine and norcodeine detection
+times in plasma and oral fluid after oral codeine
+administration.
+GC-MS cutoff,
+/H9262g/L
+Dose,
+mg/70 kg n
+Detection time,a h
+Codeine Norcodeine
+Plasma 2.5 b 60 14 12.4 /H110061.70 9.4 /H110062.07
+120 15 16.6 /H110062.57 10.3 /H110061.77
+Oral fluid 2.5 b 60 16 21.1 /H110061.70 6.0 /H110060.74
+120 18 21.6 /H110061.38 9.4 /H110061.64
+40c 60 16 7.2 /H110061.30 NA d
+120 18 7.3 /H110060.36 NA
+a Data are mean /H11006SE.
+b Method LOQ.
+c The suggested SAMHSA cutoff concentration.
+d NA, not applicable.
+Fig. 6. Mean time course (n /H1100519) of effects after 60 mg/70 kg codeine ( F), 120 mg/70 kg codeine ( Œ), and placebo (/H18554).
+Effects: (A), pupil size; (B), PCAG group (ARCI), a measure of sedation; (C), LSD (ARCI), a measure of psychotomimetic effect; (D), “feel drug”; (E), “relaxed”; (F), “high”.
+D–F are included in the SDQ. Each point represents the mean rating across all participants.
+Clinical Chemistry 48, No. 9, 2002 1493
+codeine has been reported in plasma by others after single
+(30 mg) and multiple (30 mg ever y 8 h for 7 days) oral
+doses (35 ), conjugated codeine was not detected in oral
+fluid, likely because of its high polarity and poor lipophi-
+licity.
+Few studies have evaluated the disposition of codeine
+in plasma and oral fluid and the resulting S/P ratios
+(7, 24, 25 ). Cone (24 ) reported peak oral fluid codeine
+concentrations of 183.9 and 307.6
+/H9262g/L in one participant
+0.5–0.75 h after single 60- and 120-mg intramuscular
+doses of codeine. Plasma concentrations peaked by 0.25 –
+0.5 h at concentrations of 212.4 /H9262g/L for the 60-mg dose
+and 272.4 /H9262g/L for the 120-mg dose. Despite different
+administration routes, peak plasma codeine concentra-
+tions were comparable after similar dosages; however,
+oral fluid concentrations, also collected with citric acid
+candy, were lower than our findings. Sharp et al. (7 )
+reported mean codeine concentrations of 280 /H11006250
+/H9262g/L
+in oral fluid and 60 /H1100610 /H9262g/L in plasma at 1 h and mean
+S/P ratios of 3.3 (range, 2.1 –6.5) for three participants
+after a 30-mg oral dose of codeine. Codeine S/P ratios
+were more variable than those of methaqualone, secobar-
+bital, and diphenhydramine. O’Neal et al. (25 ) reported a
+mean S/P ratio of 3.7 that remained consistent over time
+from 2 to 12 h after 30 mg of oral codeine, similar to our
+findings. In addition, a significant correlation ( r /H110050.809)
+between saliva and plasma codeine concentrations was
+observed after 2 h, suggesting that oral fluid codeine
+concentrations could be used to predict plasma concen-
+trations. However, because of oral contamination, no
+correlation was observed at earlier time points. Chen et al.
+(35 )also reported a positive correlation between oral fluid
+and plasma codeine concentrations ( r /H110050.80; P /H110210.01)
+after 30 mg of oral codeine (n /H110058) with a codeine AUC
+S/P of 2.95 /H110060.72, comparable to what we observed. In
+our study, although oral fluid codeine concentrations
+were significantly correlated to plasma codeine concen-
+trations, we concluded that it was not possible to accu-
+rately predict a plasma codeine concentration from an
+oral fluid codeine concentration because of high intra- and
+intersubject variability.
+Norcodeine S/P ratios were lower than those of co-
+deine, most likely because of differences in p K
+a and
+polarity. Drugs enter oral fluid primarily via passive
+diffusion, a process that facilitates the passage of nonion-
+ized drugs (3, 36–38 ). For acidic or basic drugs, the degree
+of ionization in the oral fluid and plasma is highly
+dependent on the p K
+a of the drug and the pH of the
+environment (8, 11–14 ). The pH of oral fluid is lower than
+that of plasma. Norcodeine, with a p Ka of 5.7 (39 ) com-
+pared with the p Ka of 8.2 for codeine (39 ), would be less
+ionized in plasma than codeine and thus less subject to
+ion trapping in the more acidic oral fluid. In addition,
+norcodeine is more polar than codeine. The oil/water
+(1-octanol/water) coefficient for codeine (37 °C, pH 7.4) is
+2.90, and that for norcodeine is 0.11 (personal communi-
+cation from Edward J. Cone). Thus, norcodeine is /H1101126
+times less lipophilic than codeine, limiting the passive
+diffusion of norcodeine from plasma to oral fluid. In
+addition, NCOD:COD ratios increased over time in both
+plasma and oral fluid, indicating a longer half-life for the
+metabolite than the parent compound.
+A major drawback to the use of oral fluid for drug
+monitoring is the variability of oral fluid pH. Mucklow et
+al. (11 ) reported that alteration of oral fluid flow rate and
+pH produced twofold changes in oral fluid drug concen-
+trations with wide inter- and intrasubject variation. Oral
+fluid pH is dependent on salivary flow rates; salivary
+gland stimulation increases bicarbonate concentration
+and oral fluid pH.
+Our mean elimination half-lives for codeine in plasma
+and oral fluid were comparable to previously reported
+estimates. A plasma t
+1/2 of 2.4 /H110060.76 h (females) and
+2.9 /H110060.32 h (males) was reported after the last of fifteen
+30-mg consecutive codeine oral doses over 5 days (40 ).A
+similar mean plasma t1/2 of 2.36 h in 19 male participants
+after a 60- or 120-mg codeine dose was noted by Rollins
+et al. (41 ). After 30-mg oral codeine, O ’Neal et al. (25 )
+observed a mean codeine t
+1/2 of 2.6 /H110060.32 h for plasma
+and 2.9 /H110060.28 h for oral fluid. Using the same dosing
+regimen, Chen et al. (35 )determined a mean t1/2 of 3.24 /H11006
+0.34 h for plasma and 3.11 /H110060.45 h for oral fluid.
+O’Neal et al. (18 ) reported higher codeine concentra-
+tions in nonstimulated oral fluid (expectoration) com-
+pared with stimulated oral fluid. Oral fluid codeine
+concentrations collected with the Salivette device or with
+acidic stimulation (a lemon drop) were lower than those
+collected by expectoration (control), 77% and 30% of
+control, respectively. Our study also compared codeine
+concentrations in oral fluid collected by three different
+methods, the first method using citric acid candy stimu-
+lation, the second a citric acid-impregnated Salivette de-
+vice, and the third a neutral Salivette cotton swab. At
+early collection time points, codeine concentrations
+tended to be higher after citric acid candy stimulation
+than with either Salivette device; however, these differ-
+ences did not reach statistical significance. Expectoration
+after acidic stimulation did produce a higher volume of
+oral fluid. Collection with the Salivette devices yielded
+smaller volumes of oral fluid and required an additional
+centrifugation step to separate oral fluid from the cotton
+swabs. However, the use of collection devices is consid-
+ered less objectionable to participants and staff and pro-
+duces a cleaner oral fluid sample.
+Codeine detection times in plasma of 12 –16 h (LOQ of
+2.5
+/H9262g/L), as reported in this study, are in agreement with
+those reported by O ’Neal et al. (25 ). A shorter mean
+plasma detection time of 5 h was observed by Vree et al.
+(28 )with a 5
+/H9262g/L cutoff after a 30-mg dose. In our study,
+the mean detection times for codeine in oral fluid were
+longer than in plasma. Thus, the advantages of monitor-
+ing codeine use in oral fluid include a longer detection
+window compared with plasma, less invasive sampling
+and discomfort, and a lower risk of infection. With the
+1494 Kim et al.: Codeine Plasma and Oral Fluid Pharmacokinetics
+higher SAMHSA-recommended cutoff of 40 /H9262g/L for
+codeine in oral fluid, a mean detection time of only 7 h
+was found after the 60 and 120 mg/70 kg doses. Use of
+this cutoff for monitoring codeine use could enable the
+identification of far fewer positive specimens than other
+types of drug testing, i.e., urine. Therefore, a lower oral
+fluid cutoff for codeine is recommended.
+In conclusion, we found that codeine was the major
+analyte detected in plasma and oral fluid. Initial detection
+times for codeine in oral fluid were comparable to those
+observed for plasma, peak concentrations were signifi-
+cantly higher, and mean detection times were 5–9 h longer
+than in plasma. Norcodeine also was detected in both
+matrices; however, morphine and normorphine were not
+measurable at the GC-MS LOQ of 2.5
+/H9262g/L after single 60
+and 120 mg/70 kg doses. Although it is difficult to predict
+plasma codeine concentrations from simultaneously col-
+lected oral fluid specimens because of intra- and intersub-
+ject variability, codeine S/P ratios were relatively constant
+after 1–2 h. Thus, the advantages of using oral fluid as a
+test matrix for codeine exposure compared with plasma
+include higher concentrations, longer detection windows,
+less invasive sampling and discomfort, and lower risk of
+infection. Oral fluid is a useful alternative matrix to
+monitor opiate use for drug treatment, workplace testing,
+criminal justice, and driving under the influence testing
+programs.
+We thank Bonnie Ladaga and Richard Taylor for expert
+assistance with the statistical analysis and pharmacody-
+namic assessments.
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+1496 Kim et al.: Codeine Plasma and Oral Fluid Pharmacokinetics

papers/PKDB00114.md

@@ -0,0 +1,16 @@
+# A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators of debrisoquine.
+
+Q Y Yue, J O Svensson, F Sjöqvist, J Säwe
+
+*British journal of clinical pharmacology* (1991)
+
+PMID: 1867958
+DOI: 10.1111/j.1365-2125.1991.tb05586.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+1. The kinetics of codeine and metabolites were studied in eight unrelated healthy Chinese subjects following a single oral dose of 50 mg codeine phosphate. The data were compared with those from eight Caucasian subjects who were matched with the Chinese group according to their metabolic ratio (MR) of debrisoquine. 2. Mean values of Cmax (445 nmol l-1) and AUC (1660 nmol l-1 h) of codeine in the Chinese were significantly higher than those in the Caucasians (292 nmol l-1 and 1010 nmol l-1 h). Thus plasma clearance was significantly lower (P less than 0.02) and the plasma half-life was longer (P less than 0.05) in the Chinese. 3. Partial clearance by glucuronidation was significantly lower (0.79 +/- 0.14 s.d. vs 1.42 +/- 0.48 s.d. 1 h-1 kg-1) in Chinese than in Caucasians. 4. The total urinary recovery of drug-related material in 48 h urine was similar in Chinese (82.2%) and Caucasians (84.4%). The recovery of unchanged codeine was significantly higher in Chinese (5.7%) than in Caucasians (3.3%). 5. The AUC ratios of codeine relative to its 6-glucuronide, morphine and norcodeine were 1:9, 35:1 and 4:1, respectively in Chinese. The corresponding ratios in Caucasians were 1:15, 50:1 and 6:1. 6. There was no significant difference between Chinese and Caucasians in the renal clearances of codeine and its primary metabolites. 7. Large interethnic differences in the kinetics of codeine have been shown. The Chinese are less able to metabolise codeine mainly because of a lower efficiency in glucuronidation.

papers/PKDB00114.pdf

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papers/PKDB00114.txt

@@ -0,0 +1,489 @@
+Br.J.clin.Pharmac.(1991),31,643-647
+A comparisonofthepharmacokineticsofcodeineandits
+metabolitesinhealthyChineseandCaucasianextensive
+hydroxylatorsofdebrisoquine
+Q.Y.YUE,J.0. SVENSSON,F.SJOQVIST&J.SAWE
+DepartmentofClinicalPharmacology,HuddingeUniversityHospital,KarolinskaInstitute,S-14186Huddinge,Sweden
+1 Thekineticsofcodeineandmetaboliteswere studiedineightunrelatedhealthy
+Chinesesubjectsfollowingasingleoraldoseof50mg codeinephosphate.Thedata
+werecomparedwiththosefromeightCaucasiansubjectswhowerematchedwiththe
+Chinesegroupaccordingtotheirmetabolicratio(MR)ofdebrisoquine.
+2 MeanvaluesofCmax(445nmoll-1)andAUC (1660nmol1-1h)ofcodeineinthe
+ChineseweresignificantlyhigherthanthoseintheCaucasians(292nmol1-1and1010
+nmol1-1h).Thusplasmaclearancewassignificantlylower(P< 0.02)andtheplasma
+half-lifewaslonger(P< 0.05)intheChinese.
+3 Partialclearancebyglucuronidationwassignificantlylower(0.79± 0.14s.d.vs1.42
+0.48s.d.Ih-'kg-')inChinesethaninCaucasians.
+4 Thetotalurinaryrecoveryofdrug-relatedmaterialin48hurinewassimilarinChinese
+(82.2%)andCaucasians(84.4%).Therecoveryofunchangedcodeinewassignificantly
+higherinChinese(5.7%)thaninCaucasians(3.3%).
+5 TheAUC ratiosofcodeinerelativetoits6-glucuronide,morphineandnorcodeine
+were 1:9,35:1and4:1,respectivelyinChinese.Thecorrespondingratiosin
+Caucasianswere 1:15,50:1and6:1.
+6 Therewas no significantdifferencebetweenChineseandCaucasiansintherenal
+clearancesofcodeineanditsprimarymetabolites.
+7 Largeinterethnicdifferencesinthekineticsofcodeinehavebeenshown.TheChinese
+arelessabletometabolisecodeinemainlybecauseofalowerefficiencyinglucuroni-
+dation.
+Keywordscodeinemetabolism
+demethylationethnicdifferences
+pharmacokineticsglucuronidation
+CaucasiansChinese
+Introduction
+Severalstudieshaveindicatedimportantinterethnic
+differencesindrugmetabolismandresponse.Recently,
+Zhouetal.(1989)reportedahighersensitivityto,but
+moreefficientmetabolismof,propranololinChinese
+comparedwithCaucasians.Anotherexampleisthefind-
+ingofalargervolumeofdistributionandgreaterplasma
+clearanceofdiphenhydramineaccompaniedbyless
+sedationanddeteriorationinpsychomotorperformance
+inOrientalsrelativetoCaucasians(Spectoretal.,1980).
+A smallerapparentvolumeofdistributionofdiazepam
+hasbeenreportedinChinese,probablyreflectingtheir
+lowerbodymass(fatandstature),comparedwiththatin
+Caucasians(Ghoneimetal.,1981;Kumanaetal.,1987).
+Furthermore,aslowermetabolismofdiazepamhas
+recentlybeenshowninChinese,andadifferenceinthe
+substratespecificityofS-mephenytoinhydroxylasehas
+beensuggested(Zhangetal.,1990).Theclearanceof
+paracetamolwasfoundtobelowerinAsiansthanin
+Europeans,probablytheresultofenvironmentaldif-
+ferences(Mucklowetal.,1980).Inaddition,differences
+existbetweenOrientalandCaucasianpopulationsinthe
+frequencyofpoormetabolisersofdrugsthatare
+metabolisedbydebrisoquinehydroxylase(Kalowetal.,
+1980;Louetal.,1987;Yueetal.,1988,1989a,b)andby
+S-mephenytoinhydroxylase(Horaietal.,1989;
+Nakamuraetal.,1985).
+Correspondence:DrJ.Sawe,DepartmentofClinicalPharmacology,HuddingeUniversityHospital,KarolinskaInstitute,S-14186
+Huddinge,Sweden
+643
+AD0NIS030652519100115K
+644 Q.Y.Yueetal.
+Codeineismetabolisedmainlybyglucuronidationto
+codeine-6-glucuronide(C6G);minorroutesofmeta-
+bolismincludeO-demethylationtomorphine(M)and
+N-demethylationtonorcodeine(NC)(Adleretal.,1955;
+Guayetal.,1987,1988;Rogersetal.,1982;Yueetal.,
+1989b,c).We havepreviouslyreportedsignificantdif-
+ferencesintheurinaryexcretionofcodeineaswellasof
+C6Gin133healthyChinesecomparedwith149Swedish
+Caucasians(Yueetal.,1989b).Inordertounderstand
+thisinterethnicdifferencemoreclearly,wehavestudied
+thepharmacokineticsofcodeineanditsmetabolites
+withaspecifich.p.l.c.methodinChinesesubjectsand
+comparedthedatawiththoseobtainedinCaucasians
+(Yueetal.,1991).
+Methods
+EightunrelatedhealthyChinese(threewomenandfive
+men)whohavebeenstayinginSwedenasvisiting
+scientistsforlessthan5yearsparticipatedinthestudy.
+Theywerepreviouslyphenotypedwithdebrisoquine
+usingthemethodofLennardetal.(1977).Theirindivi-
+dualcharacteristicsanddebrisoquinemetabolicratios
+areshowninTable1.Nonewastakinganymedication.
+Onevolunteersmoked(10cigarettesperday)andall
+wereconsideredtobehealthyonthebasisofphysical
+examinationandbloodtests.Allsubjectsgavetheir
+writteninformedconsenttoparticipateinthestudy,
+whichwasapprovedbytheEthicsCommitteeofthe
+HuddingeHospital.
+TheCaucasiancontrolsubjectsaredescribedindetail
+inacompanionpaper(Yueetal.,1991).Theywereall
+extensivehydroxylatorsofdebrisoquine.
+Followinganovernightfast,eachsubjectreceiveda
+singleoraldoseof50mgcodeinephosphate(two25mg
+tablets,Kodein®,ACO).A standardlunchwaspro-
+vided4hafterdrugintake.Bloodsampleswerecollected
+inheparinizedVacutainer®tubesbeforeandat0.17,
+0.33,0.5,0.67,1,1.5,2,3,4,5,7,9,11and24hafterthe
+dose.Thebloodsampleswerecentrifugedandplasma
+wasstoredat-20°Cuntilanalysis.Serialurinesamples
+werecollectedat0-2,2-4,4-6,6-8,8-10,10-12,12-24,
+24-36and36-48h.UrinevolumesandpHweremeasured
+andaliquotswerestoredat-20°Cuntilanalysed.
+Table1 Individualcharacteristicsanddebrisoquinemetabolic
+ratiosofeightChinesehealthyvolunteers
+Body
+Age weight Debrisoquine
+Subject (years)Sex (kg) metabolicratio
+1 45 M 63 0.41
+2 27 M 59 0.24
+3 38 M 60 0.51
+4 34 M 81 1.40
+5 33 F 44 3.86
+6 30 F 57 0.20
+7 36 F 59 0.88
+8 32 M 61 4.14
+Mean 34 61 1.46
+s.d. 5 10 1.62
+Codeineanditssevenknownmetabolitesmorphine
+(M),M-3-glucuronide(M3G),M-6-glucuronide(M6G),
+normorphine(NM),codeine-6-glucuronide(C6G),
+norcodeine(NC),andNC-glucuronide(NCG)were
+measuredinplasmaandurineusingion-pairhighper-
+formanceliquidchromatographyaccordingtoamodi-
+ficationofthemethodofSvensson(1986)(Yueetal.,
+1989b,c).
+Pharmacokineticcalculationswereperformedas
+describedbyYueetal.(1991).
+Metabolicratios(MRs)werecalculatedfromboth
+plasmaandurinedataasfollows:
+MRglucuronidation= codeine/C6G;
+MRO-demethylation=codeine/(M+M3G+M6G+NM);
+MRN-demethylation=codeine/(NC+NCG+NM).
+TheunpairedStudent'st-testandaU-testfor0-
+demethylationdatawereusedforcomparisonsbetween
+thetwoethnicgroups.
+Results
+SignificantlyhigherCmax(445±120and292±95nmol
+F-;P<0.02)andhigherAUCvalues(1660±300and
+1010±390nmol1-1h;P<0.005)(Figure1)andlower
+plasmaclearances(1.26±0.22and2.10±0.841h-'kg-';P<0.02)wereobservedintheChinesecomparedwiththe
+Caucasiansubjects.Theplasmahalf-lifeofcodeinewas
+longerintheChinesethanintheCaucasians(2.94±0.49
+and2.34± 0.58h;P < 0.05,Table3).Therewasno
+differencebetweenChineseandCaucasiansintheAUCof
+C6G(Figure2).However,thehalf-lifeofthismetabolite
+waslongerinChinese(P< 0.05,Table3).Thepartial
+metabolicclearancebyglucuronidationwassignificantly
+lower(0.79±0.14and1.42±0.481h-1kg-1;P<0.005)
+(Table2),whiletheMRsofglucuronidationcalculated
+frombothAUCandurinevalueswerehigher(0.11±0.04
+and0.067±0.024forAUC;P<0.01;0.095+0.04and
+0.049±0.024forurine;P < 0.02)intheChinese.The
+correlationcoefficientsbetweenMRAUcandMRuineforglucuronidationwere0.78inChineseand0.93in
+Caucasians.
+1000
+zE
+Co
+ccCu
+0
+C:
+0
+co
+EU)
+Co
+100 2 4 6 8 10 12
+Time(h)
+Figure1 Plasmaconcentration-timecurvesofcodeinein
+eightChinese(U)andeightCaucasian(*)subjectsaftera
+singleoral50mgdoseofcodeinephosphate(mean±s.d.).
+Ethnicdifferencesincodeinemetabolism645
+000
+10
+k1b
+0 10 20
+I A
+10 IX."3' -90
+Time(h)
+Figure2 Plasmaconcentration-timecurvesofcodeineanditsmetabolitesinarepresentativeCaucasianextensivemetaboliser
+(EM)ofdebrisoquine(a)andaChinesesubject(b)afterasingleoral50mgdoseofcodeinephosphate.DataforNCandNCG
+wereomittedforthesakeofclarity.
+Table2 Age,bodyweight,somekineticparametersandMRsofcodeineinChinese
+andCaucasianEM (mean±s.d.)
+Chinese Caucasiansa p
+Age(years) 34.4±5.5 33.4±3.9 NS
+DBMRb 1.46±1.62 1.60±1.72 NS
+Bodyweight(kg) 61±10 66±10 NS
+Plasmaclearance(1h-1kg-1) 1.26±0.22 2.10±0.84 < 0.02
+Partialmetabolicclearance(1h-1kg-')Glucuronidation 0.79±0.14 1.42±0.48 < 0.005
+O-demethylation 0.091±0.035 0.124±0.098 NS
+N-demethylation 0.113±0.039 0.174±0.079 NS
+aDataofCaucasianextensivemetabolisers(EM)ofdebrisoquinearefromYueetal.
+(1991).
+bDB MR:debrisoquinemetabolicratio.
+Table3 Kineticparametersofcodeineanditsthreemajormetabolitesaftersingleoral50mgdoseofcodeinephosphateinChineseand
+CaucasianEMa(mean±s.d.)
+Codeine C6G M NC
+ChineseCaucasianP ChineseCaucasianP ChineseCaucasianP ChineseCaucasianP
+Cmax(nmoll-l) 445 292 < 0.02 3090 3610 NS 16.6 8.4 NS 65 41 NS
+±120 ±95 ±512 ±640 ±11.9 ±8.2 ±32 ±18
+tmax(h) 1.06 1.0 NS 1.54 1.21 NS 0.81 0.83 NS 1.11 0.88 NS
+±0.42 ±0.38 ±0.39 ±0.33 +0.34 ±0.25 ±0.52 ±0.32
+AUC(nmol1-1h) 1660 1010 <0.005 15200 15200 NS 48 20 NS 410 163 NS
+±303 ±391 ±2780 ±2690 ±39 ±20 ±329 ±87
+t,2(h) 2.94 2.34 <0.05 3.44 2.79 <0.05 2.72 2.10 NS 3.75 2.62 NS
++0.49 ±0.58 ±0.50 ±0.50 1.49 1.61 1.83 1.32
+CLR(1h-1kg-') 0.047 0.051 NS 0.095 0.089 NS 0.13 0.16 NS 0.18 0.20 NS
+0.023 0.023 0.016 0.020 0.042 0.099 0.093 0.092
+aDataofCaucasianextensivemetabolisers(EM)ofdebrisoquinearefromYueetal.(1991).
+TheurinaryMR ofN-demethylationwashigherin
+Chinese(0.67±0.20)thaninCaucasians(0.43±0.25)
+(P<0.05).However,therewasnodifferencebetween
+thetwoethnicgroupsinpartialmetabolicclearanceby
+N-demethylation(Table2).
+Nosignificantdifferencewasobservedwithregardto
+theO-demethylationreactionbetweenthetwoethnic
+groups.Bothgroupsshowedlargeinterindividualvaria-
+tioninO-demethylation(Tables3and4).
+Theurinaryrecoveryofdrug-relatedmaterialin48h
+urinewassimilarinChinese(82.2±15.6%ofdose)and
+Caucasians(84.4± 15.9%;P > 0.05,Table4).The
+recoveryofunchangedcodeine,however,wassignifi-
+cantlyhigherinChinesethaninCaucasians(5.71±1.98
+and3.33± 1.52%ofdose;P < 0.02).Therewasno
+significantdifferenceintheurinaryrecoveryofthe
+metabolites(Table4)norinrenalclearancesofcodeine
+anditsmetabolites(Table3).
+id
+Li
+..
+I...'U,;
+ _
+., e.
+
+646 Q.Y.Yueetal.
+Table4 Urinaryrecovery(%dose)over48hofcodeineandits
+metabolites
+Chinese CaucasianSa
+(n=8) (n=8)
+Cod 5.71±1.98 3.33±1.52*
+C6G 62.0±6.68 68.4±7.67
+NC 3.26±1.62 2.32±1.62
+NCG 3.70±1.64 4.36±0.68
+M3G 4.20±2.13 3.46±2.74
+M6G 0.98±0.51 0.83±0.63
+NM 2.02±0.83 1.50±0.87
+Mor 0.32±0.20 0.18±0.16
+Total 82.2±15.6 84.4±15.9
+*Student'st-test(P<0.02)betweenChineseandCaucasians.
+aDataforCaucasianextensivemetabolisers(EM)of
+debrisoquinearefromYueetal.(1991).
+InChinese,theAUC ratiosofcodeinerelativeto
+C6G,M andNCwere1:9,35:1and4:1,respectively.
+ThecorrespondingvaluesinCaucasianswere1:15,
+50:1and6:1(Table3).
+FouroftheeightChinesevolunteersexperienced
+slighttirednessordizzinessandoneoftheCaucasians
+reportedtiredness.
+Discussion
+Amainaimofthisstudywastocomparethecapacityto
+glucuronidatecodeineinChineseandCaucasiansub-
+jects.ItisknownthatO-demethylationofcodeineco-
+segregateswiththehydroxylationofdebrisoquineboth
+invivo(Chenetal.,1988;Yueetal.,1988,1989a,c)and
+invitro(Dayeretal.,1988;Mortimeretal.,1990).Itis
+alsoknownthatthefrequencyofpoormetabolisersof
+thesedrugsisdifferentinChineseandCaucasianpopu-
+laionswithregardtobothphenotypingandgenotyping
+determinations(Louetal.,1987;Yueetal.,1989a,b).
+InanearlierstudyincludingCaucasians,wehavedemon-
+stratedthatpoorhydroxylatorsofdebrisoquineexcreted
+moreC6GandNCthanextensivemetabolisersinurine
+collected8hafteroralcodeine,andthatthisphenomenon
+mightbeaconsequenceofalowexpressionofthe0-
+demethylationpathway(Yueetal.,1989c).Toavoidthis
+geneticinfluenceonthepharmacokineticsofcodeine,
+wematchedourtwoethnicgroupsaccordingtotheir
+debrisoquineMRs(Table3).Possiblegeneticdifferencesintherenaltubular
+secretionofdebrisoquinehavebeensuggestedsincethe
+meanamountofdrugthatisexcretedunchangedshows
+widepopulationdifferences(Kalow,1984).Inthepresent
+study,however,wedidnotobserveanysignificantdif-
+ferencebetweenthetwoethnicgroupsintherenal
+clearanceofcodeinenoranyofitsmetabolites(Table3).
+Inaddition,therewerehigherCmaxandAUCvaluesand
+lowerplasmaclearancesintheChinesesubjects,in-
+dicatingthattheywerelessabletometabolisecodeine.
+Thenonsignificant8%differenceinmeanbodyweights
+doesnotinfluencetheinterpretationastherewasa
+statisticallysignificant(P<0.02)decreasealsoinplasma
+clearanceperkgbodyweightintheChinese.Inaddition,
+thepartialmetabolicclearancebyglucuronidationwas
+significantlylowerintheChinesethanintheCaucasians,
+confirminganearliersuggestionthatChineseareless
+efficientglucuronidatorsofcodeine(Yueetal.,1989b).
+Thehalf-lifeofC6Gwhichparalleledthatofcodeine
+waslongerinChinese.Thissuggeststhattheformation
+ofC6Grate-limitsitselimination.Volumesofdistribution
+havebeenshowntobedifferentbetweenOrientals
+andCaucasiansfordiazepamanddiphenhydramine
+(Ghoneimetal.,1981;Spectoretal.,1980),andthis
+possibilityneedstobeinvestigatedforcodeineand
+C6G.
+Themechanismbehindtheseethnicdifferences
+remainstobestudied.Glucuronidationreactionsare
+catalysedbyagroupofisoenzymeswhichhavedifferent
+butoverlappingspecificities.Glucuronidationofcodeine
+hasbeenshowntobeinducedbysmokingandbyoral
+contraceptiveuse(Yueetal.,1989b),andtobeinhibited
+invitrobycommonlyuseddrugssuchasM,chloram-
+phenicol,diazepamandamitriptyline(Yueetal.,1990a).
+Thisinvitrostudyhasalsodemonstratedacorrelation
+betweentheglucuronidationofcodeineandthatofM.
+Hencethefindingsofthepresentstudywithcodeine
+mightbepredictivefortheglucuronidationofM.
+UrinepHhasbeenfoundtocorrelatedirectlywiththe
+urinaryexcretionofC6GandNCG andinverselywith
+thatofcodeine.However,therewasnosignificant
+differenceinurinepHbetween149Caucasiansand133
+Chinesehealthyvolunteers(Yueetal.,1989b).The
+ChinesevolunteersinthisstudyatemoreChinesefood
+thanWesternfoodandkepttheChinesehabitsof
+drinkingmoreteathancoffee.Thus,environmental
+factorscouldcontributetotheobservedinterethnic
+differenceinglucuronidation.ThehigherurinaryMR
+forN-demethylationinChineseobservedinthisstudy
+wasconsistentwiththefindingofapreviouspopulation
+study(Yueetal.,1989b).Thefailuretoshowany
+differencebetweenChineseandCaucasiansinplasma
+MR orpartialclearancebyN-demethylationmayreflect
+therelativelysmallsamplesizeofthepresentstudy.
+Severalmetabolitesofcodeine,includingM,M6G,
+NM andNC,havebeenshowntohaveanalgesiceffects
+(Lasagna& DeKornfeld,1958;Miller& Anderson,
+1954;Osborneetal.,1988;Sanfilippo,1948).Onthe
+otherhand,codeineitselfcouldaccountformostofits
+analgesicorsideeffectsinviewofitsrelativelyhigh
+plasmaconcentration(Quidingetal.,1986).We have
+observeda50%increaseinCmaxandAUC inthe
+Chinesesubjects,whichmightbeofsomeclinicalimpor-
+tance.Itmaybesignificantthatlowerdosesofcodeine
+havebeenrecommendedforChinesesubjects(Jiang,
+1984)comparedwithCaucasians.Theanalgesicpotency
+ofC6Ginunknown.
+Inconclusion,we haveshownalargeinterethnic
+differenceinthepharmacokineticsofcodeine.Chinese
+subjectsarelessabletometabolisethisdrug,duetoa
+lowerefficiencyinglucuronidation.
+TheworkwassupportedbytheSwedishResearchCouncil
+(3902)andtheSwedishCancerSociety(1910-B88-O1V).Samplesofcodeinemetaboliteswerekindlyprovidedbythe
+NationalInstituteofDrugAbuse,USA.
+Ethnicdifferencesincodeinemetabolism647
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+(Received24July1990,
+accepted6December1990)

papers/PKDB00115.md

@@ -0,0 +1,16 @@
+# Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine.
+
+Q Y Yue, J Hasselström, J O Svensson, J Säwe
+
+*British journal of clinical pharmacology* (1991)
+
+PMID: 1867957
+DOI: 10.1111/j.1365-2125.1991.tb05585.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+1. The kinetics of codeine and seven of its metabolites codeine-6-glucuronide (C6G), norcodeine (NC), NC-glucuronide (NCG), morphine (M), M-3 (M3G) and 6-glucuronides (M6G), and normorphine (NM) were investigated after a single oral dose of 50 mg codeine phosphate in 14 healthy Caucasian subjects including eight extensive (EM) and six poor (PM) hydroxylators of debrisoquine. The plasma and urine concentrations of codeine and the metabolites were measured by h.p.l.c. 2. The mean area under the curve (AUC), half-life and total plasma clearance of codeine were 1020 +/- 340 nmol l-1 h, 2.58 +/- 0.57 h and 2.02 +/- 0.73 l h-1 kg-1, respectively. There were no significant differences between EM and PM in these aspects. 3. PM had significantly lower AUC of M3G, the active metabolites M6G, NM and M (P less than 0.0001), and lower partial metabolic clearance by O-demethylation (P less than 0.0001). In contrast, the PM had higher AUC of NC (P less than 0.05) than the EM. There was no difference between PM and EM in the AUC of C6G and NCG, nor in the partial clearances by N-demethylation and glucuronidation. 4. Among EM, the AUC of C6G was 15 times higher than that of codeine, which in turn was 50 times higher than that of M. The AUCs of M6G and NM were about 6 and 10 times higher than that of M, respectively. The partial clearance by glucuronidation was about 8 and 12 times higher than those by N- and O-demethylations, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

papers/PKDB00115.pdf

@@ -0,0 +1,3 @@
+version https://git-lfs.github.com/spec/v1
+oid sha256:c2a29ad004ff4600eff96d82aae0d02b73c3fc58e2e703c97f09ba829dcfcdae
+size 1304329

papers/PKDB00115.txt

@@ -0,0 +1,720 @@
+Br.J.clin.Pharmac.(1991),31,635-642
+PharmacokineticsofcodeineanditsmetabolitesinCaucasian
+healthyvolunteers:comparisonsbetweenextensiveandpoor
+hydroxylatorsofdebrisoquine
+Q.Y.YUE,J.HASSELSTROM,J.0.SVENSSON&J.SAWE
+DepartmentofClinicalPharmacology,HuddingeUniversityHospital,KarolinskaInstitute,S-14186Huddinge,Sweden
+1 Thekineticsofcodeineandsevenofitsmetabolitescodeine-6-glucuronide(C6G),
+norcodeine(NC),NC-glucuronide(NCG),morphine(M),M-3(M3G)and6-glucu-
+ronides(M6G),andnormorphine(NM)wereinvestigatedafterasingleoraldoseof50
+mgcodeinephosphatein14healthyCaucasiansubjectsincludingeightextensive(EM)
+andsixpoor(PM)hydroxylatorsofdebrisoquine.Theplasmaandurineconcentrations
+ofcodeineandthemetabolitesweremeasuredbyh.p.l.c.
+2 Themeanareaunderthecurve(AUC),half-lifeandtotalplasmaclearanceofcodeine
+were1020±340nmol1-1h,2.58±0.57hand2.02±0.731h-1kg-1,respectively.
+TherewerenosignificantdifferencesbetweenEM andPM intheseaspects.
+3 PMhadsignificantlylowerAUCofM3G,theactivemetabolitesM6G,NM andM (P
+<0.0001),andlowerpartialmetabolicclearancebyO-demethylation(P<0.0001).In
+contrast,thePM hadhigherAUC ofNC (P< 0.05)thantheEM.Therewasno
+differencebetweenPM andEM intheAUC ofC6GandNCG,norinthepartial
+clearancesbyN-demethylationandglucuronidation.
+4 AmongEM,theAUCofC6Gwas15timeshigherthanthatofcodeine,whichinturn
+was50timeshigherthanthatofM.TheAUCsofM6GandNM wereabout6and10
+timeshigherthanthatofM,respectively.Thepartialclearancebyglucuronidationwas
+about8and12timeshigherthanthosebyN-andO-demethylations,respectively.
+5 Thetotalrecoveryofdrug-relatedmaterialin48hurinecollectionsrangedfrom71%
+to106%ofthedoseanddidnotdifferbetweenEM andPM.Sixpercentofthedose
+wasO-demethylatedinEM andthemajorityofthemetabolitesproducedthroughthis
+pathwaywereconjugated.UnconjugatedM accountedforlessthan0.2%ofthedose.
+InPM,only0.33%ofthedosewasmetabolizedbyO-demethylationandM was
+negligible(0.001%ofthedose).However,PM hadasignificantlyhigherrecoveryof
+NC(P<0.001)thanEM.TherewasnosignificantdifferencebetweenEM andPMin
+therecoveryofcodeine,C6GandNCG,andintherenalclearanceofcodeineoranyof
+itsmetabolites.
+6 DatafromachronicdosingstudyincludingthreeEM andthreePM confirmedthe
+resultsofthesingledosestudy.
+7 Theclinicallyimportantfindingswerethenegligibleplasmaconcentrationofthe0-
+demethylatedactivemetabolitesM6G,NM andM inPM,andtherelativelyhigh
+concentrationsofM6GandNM inEM.Consideringthelowplasmaconcentrationof
+M aswellasthepotentanalgesiceffectsofM6GandNM,thelattercompoundsmight
+playanimportantroleintheanalgesiceffectofcodeine.
+Keywordscodeinemetabolismactivemetabolitespharmacokinetics
+pharmacogeneticsCaucasiandebrisoquinephenotype
+Correspondence:DrJ.Sawe,DepartmentofClinicalPharmacology,HuddingeUniversityHospital,KarolinskaInstitute,S-14186
+Huddinge,Sweden
+635
+AD0NIS0306525191001147
+636 Q.Y.Yueetal.
+Introduction
+Codeineisacommonlyusedanalgesicandantitussive
+drug.Itspharmacokineticsinman(Findlayetal.,1977,
+1978;Guayetal.,1987;Quidingetal.,1986)andthe
+influenceofsmoking(Rogersetal.,1982),alcohol
+(Boddetal.,1987)aswellasrenaldisease(Guayetal.,
+1988)havebeeninvestigated.Thehypothesisthatco-
+deinemayexertitsmoderateanalgesicpotencythrough
+partialbiotransformationtomorphine(M)hasbeen
+proposed(Sanfilippo,1948),andthebiotransformation
+ofcodeinetoM inmanbyO-demethylationhasbeen
+demonstrated(Findlayetal.,1978;Guayetal.,1987,
+1988;Quidingetal.,1986;Rogersetal.,1982).Apart
+fromM,twoothermetabolitesofcodeineO-demeth-
+ylation,morphine-6-glucuronide(M6G)andnormor-
+phine(NM),havealsobeenshowntobeactive.Much
+strongeranalgesicpotencyhasbeenreportedforM6G
+comparedwithM (Handetal.,1987;Joeletal.,1985;
+Osborneetal.,1988;Pauletal.,1989;Shimomuraetal.,
+1971;Yoshimuraetal.,1973).Figure1showsthemajor
+metabolicpathwaysofcodeine.
+Itiswellrecognisedthatsomedrugsaremetabolised
+bypathwaysthatareundermonogeniccontrol.Among
+thebeststudiedpathwaysshowinggeneticpolymorphism
+isdebrisoquine-typehydroxylation;5-10%ofCaucasians
+areclassifiedas'poorhydroxylators'(PM)whilethe
+remainderare'extensivehydroxylators'(EM)(Mahgoub
+etal.,1977;Steineretal.,1988).O-demethylationof
+codeine,leadingtotheformationoftheactivemetab-
+olitesM,M6GandNM,hasbeenfoundtoco-segregate
+withthedebrisoquineoxidationpolymorphism(Chenet
+al.,1988;Dayeretal.,1988;Yueetal.,1988,1989a,
+1989b).Wehavenowstudiedthepharmacokineticsof
+codeineanditsmetabolitesinPM andEM ofdebriso-
+quine.
+Methods
+FourteenhealthyCaucasians,includingeightEM and
+sixPM ofdebrisoquine,participatedinthissingledose
+studywhichwasapprovedbytheEthicsCommitteeof
+HuddingeUniversityHospital.Informedconsentwas
+obtainedfromallsubjects.Thesubjectcharacteristics
+anddebrisoquinemetabolicratios(MR)arepresented
+inTable1.Eachsubjectwasphenotypedwithasingle
+10mgoraldoseofdebrisoquinehemisulphate(Declinax,
+Hoffmann-LaRoche).Theratioofparentdrugandthe
+4-hydroxy-metabolite(D/4-OH-D)wasmeasuredinan
+aliquotofa8hurinecollection.Debrisoquineand
+4-OH-Dweremeasuredbygaschromatographywith
+flame-ionizationdetectionaccordingtoLennardetal.
+(1977).APMwasdefinedashavingaMR >12.6(Evans
+etal.,1980).
+Onaseparateoccasion,thesubjectsweregivena
+singleoraldoseof50mgcodeinephosphate(Kodein®,ACO DrugsAB,Sweden)followinganovernightfast.
+Bloodsamples(10ml)wereobtainedthroughanin-
+dwellingintravenouscatheterintoheparinizedVacu-
+tainertubesbeforeand0.17,0.33,0.5,0.67,1,1.5,2,
+3,4,5,7,9,11and24hafterthedose.Thesampleswere
+centrifugedandtheplasmawasstoredat-20°Cuntil
+analysis.Serialurinesampleswerecollectedfor48h
+from0-2,2-4,4-6,6-8,8-10,10-12,12-24,24-36and
+36-48h.UrinevolumesandpHweremeasuredand
+aliquotswerestoredat-20°Cuntilanalyzed.
+Anothersixhealthyvolunteers,includingthreeEM
+withMRsbetween0.34and0.68(aged27to33years)
+andthreePMwithMRsbetween37and64(aged28to
+41years),receivedmultipledosesofcodeine.Following
+thefirstdose,bloodandurinesampleswerecollectedfor
+24h.Fromday2(after24h),codeine(50mg)was
+administeredregularlyevery6hforninedoses.Blood
+sampleswerecollectedfor30handurinesamplesfor48
+hafterthelastdose.
+Codeineanditssevenknownmetabolitesmorphine
+(M),M-3-(M3G),andM-6-glucuronide(M6G),nor-
+morphine(NM),codeine-6-glucuronide(C6G),nor-
+codeine(NC),NC-glucuronide(NCG)inbothplasma
+andurineweremeasuredusingion-pairhighper-
+formanceliquidchromatographybyamodificationof
+themethodofSvensson(1986)asdescribedinYueetal.
+(1989a).ForthesourcesofallthechemicalsseeYueet
+al.(1989a)andSvensson(1986).
+Theareaunderthecurve(AUC)ofcodeinewas
+calculatedbythelineartrapezoidalruleandextrapolated
+Codeineglucuronide
+tNCH,
+HH
+O-demethylationCH3°O0° 'OHN-demethylation
+NC,CodeineN-CH3 NH
+Glucuronides H HH Glucuronide
+(M3G, M6G) (NCG)
+HO 0 OH CH3-0 0 OH
+Morphine NH Norcodeine
+HH
+N-demethylation O-demethylation
+HO OH
+Normorphine
+Figure1 Themajormetabolicpathwaysofcodeine.M3G = Morphine-3-glucuronide;M6G = Morphine-6-glucuronide;
+NCG = Norcodeineglucuronide.
+Codeinemetabolismanddebrisoquinephenotype637
+toinfinitybyuseofthelastmeasuredplasmaconcentra-
+tionandtheeliminationrateconstant(Xl),whichwas
+determinedbylog-linearregressionanalysisofthe
+terminalconcentration-timepoints.Theeliminationhalf-
+life(t½,2)wasobtainedbydividingln2by,\.Theplasma
+clearance(CL)ofcodeinewascalculatedfromtheratio
+ofdoseandAUC.Renalclearance(CLR)andmetabolic
+clearanceofcodeinethroughdifferentpathwayswere
+calculatedusingthefollowingequations:
+CLR = Ae(codeine),_t2/AUCt,-t2
+CLglucuronidation= Ae(C6G)t,_t2/AUCt,-t2
+CLO demethylation =
+Ae(M+M3G+M6G+NM)tl-2/AUCtI- t2
+CLN-demethylation= Ae(NC+NCG+NM)t_t2/AUCt,-t2
+Aet,1t2istheurinaryrecoveryofcompoundoverthe
+urinecollectionintervalt1_t2,andAUCt,-t2isthearea
+undertheplasmacodeineconcentrationvstimecurve
+overtheurinecollectionintervalt1-t2.Itwas assumed
+thatcodeineisabsorbedcompletelyfromtheg.i.tract
+(Bechtel& Sinterhauf,1978).Anotherassumptionwas
+thatthefinaleliminationofthemetabolitesoccursonly
+byrenalexcretion.Maximumplasmaconcentrations
+(Cmax)andtimetoattainCmax(tmax)were estimated
+fromobservedplasmaconcentrationvstimedata.
+TheunpairedStudent'st-test(orU-testforO-de-
+methylationdata)wasusedforthecomparisonbetween
+thetwophenotypicgroups.
+Results
+Theindividualkineticparametersin14subjects(eight
+EM andsixPM)areshowninTable1.TheAUC of
+codeinerangedfrom537to1728(mean± s.d.= 1020+
+340)nmol1-1hinallthesubjects.Therangesofplasma
+codeinehalf-lifeandplasmaclearancewere between
+1.55and3.29(2.58± 0.57)handbetween1.23and3.95
+(2.02± 0.73)1h-1kg-'respectively.
+Representativeplasma-concentrationvstimecurves
+forcodeineanditsmetabolitesinone PM andone EM
+areshowninFigure2andtheaverageAUC valuesforall
+subjectsarelistedinTable2.Therewas no difference
+betweenEM andPM intheAUC andplasmaclearance
+ofcodeine(Tables1and2).However,therewere pro-
+nounceddifferencesintheformationofmetabolites
+betweenEM andPM (Figure2andTable2).PM had
+significantlylowerAUC valuesofM3G,M6G,NM and
+M (P< 0.0001),andlowerpartialmetabolicclearance
+byO-demethylation(P< 0.0001,Table1and2).Fiveof
+sixPM didnothaveadetectableamountofM andone
+PM hadanAUC ofM lessthan2nmoll-1h.TheAUC
+valuesofM6G andNM were more than20xlowerin
+PM comparedtoEM (Table2).
+Incontrast,thePM hadhigherAUC valuesofNC (P
+< 0.05)thantheEM (Table2).Therewas nosignificant
+differencebetweenPM andEM intheAUCsofC6G
+andNCG,norinthepartialclearancesbyN-demethyl-
+ationandglucuronidation(Tables1and2).
+Table1 Subjectcharacteristics,debrisoquineratioandkineticparametersofcodeineand
+metabolitesafterasingleoral50mg(123,umol)ofcodeinephosphateto14healthyCaucasian
+subjects(eightEM andsixPM)
+SubjectAgelsex/weightDBMRa Cmax tmaxt½/2CL Partialmetabolicclearanceb
+O-dem N-dem Glucu
+(years)(kg) (nmol1-')(h) (h)(1h-1kg-l)(1h-1kg-)(lh-'kg-')(lh-'kg-')
+EM
+1 35/F/58 0.34 462 0.5 1.23 1.23 0.09 0.09 0.77
+2 40/F/68 0.51 272 1.5 2.51 1.38 0.09 0.11 0.89
+3 31/M/70 0.46 250 1.0 2.91 1.88 0.25 0.17 1.42
+4 38/F/58 0.21 206 1.5 1.58 3.95 0.27 0.33 2.24
+5 31/M/78 0.43 165 1.0 2.88 2.13 0.20 0.14 1.34
+6 29/M/80 3.10 327 0.5 1.55 2.39 0.06 0.22 1.31
+7 31/F/65 3.30 272 1.0 2.84 1.83 0.04 0.12 1.52
+8 32/F/52 7.48 378 1.0 1.89 2.04 0.01 0.21 1.86
+Mean 33l-l66 1.98 292 1.0 2.43 2.10 0.12 0.17 1.42
+s.d. 34/-/10 2.57 95 0.380.58 0.84 0.10 0.08 0.48
+PM
+9 27/F/67 250 432 0.673.29 1.24 0.002 0.16 0.81
+10 40/F/67 37 179 1.5 2.73 2.36 0.004 0.16 1.47
+11 23/F/55 26 173 0.673.20 2.81 0.017 0.38 2.18
+12 27/M/85 97 154 1.0 2.79 1.73 0.009 0.15 1.60
+13 31/F/61 380 249 1.0 2.21 2.11 0.004 0.27 1.50
+14 31/M/78 31 505 0.333.18 1.24 0.004 0.15 1.03
+Mean 30/-/69 137* 282 0.862.90 1.92 0.007* 0.21 1.43
+s.d. 6/-/11 146 150 0.400.41 0.63 0.006 0.09 0.48
+aDBMR = debrisoquinemetabolicratio;
+bO-dem= O-demethylation;N-dem= N-demethylation;Glucu= glucuronidation;
+*P<0.0001.U-testbetweenEM andPM.
+638 Q.Y.Yueetal.
+a
+ ~1 A.!
+0. 0 ..: 0 10 20 30
+Figure2 Plasmaconcentration-timecurvesofcodeineanditsmetabolitesinaPM(a)andEM (b)ofdebrisoquineafterasingle
+oraldoseof50mgcodeinephosphate.(DataforNCandNCGwereexcludedforthesakeofclarity.)
+Table2 PlasmaAUCandurinaryrecoveryofcodeineanditsmetabolitesineightEM andsix
+PMofdebrisoquine(mean±s.d.)a
+PlasmaAUC(nmol1-h) Urinaryrecovery(%ofdose)
+EM pMb EM PMb
+Codeine 1010±391 1020±292 3.33±1.52 3.56±0.85
+C6G 15200±2690 17700±2710 68.4±7.7 75.3± 11.3
+NC 163±87 289±117* 2.3±1.6 5.7±1.2**
+NCG 772±351 976±380 4.4±0.7 5.3±1.7
+M3G 807±808 25.4±10.4***3.5±2.7 0.16±0.07***
+M6G 117±95 5.2±2.8***0.83±0.63 0.14±0.12***
+M 20±20 <2c 0.18±0.16 0.001±0.002***
+NM 191±157 < 9*** 1.50±0.87 0.029±0.05***
+Total 84.4±15.9 90.2±15.3
+aTheU-testwasusedtocompareEM andPMwithrespecttoM3G,M6G,M andNM andthe
+t-testwasusedfortheremainingmetabolites.
+bDifferencebetweenEM andPM *(P<0.05);**(P<0.001);***(P<0.0001).
+StatisticcomparisonswerenotpossiblesinceM couldbedetectedinonlyonePM.
+AmongEM,thepartialclearancebyglucuronidation
+(Table1)was more than8timeshigherthanthatbyN-
+demethylationandabout12timeshigherthanthatby0-
+demethylation(Table1).TheAUCofC6Gwas15times
+greaterthanthatofcodeine,whichinturnwas50times
+greaterthanthatofM.TheAUC valuesofactiveM6G
+andNM wereabout6and10timeshigherthanthatofM,
+respectively(Table2).
+In48hurinecollections,thetotalrecoveryofdrug-
+relatedmaterialrangedfrom71%to106%ofthedose
+anddidnotdifferbetweenEM andPM (Table1).The
+patternofurinaryrecoverywassimilartothatofplasma
+AUC forbothcodeineandthemetabolites(Table2).
+Sixpercentofthedosewas 0-demethylatedinEM and
+themajorityofthemetabolitesformedbythispathway
+wereconjugated;M accountedforlessthan0.2%ofthe
+dose.InPM,only0.33%ofthedosewasmetabolisedby
+0-demethylationandM recoverywasnegligible(0.001%
+ofthedose).However,PM hadasignificantlyhigher
+recoveryofNC (P< 0.001)thantheEM (Table2).No
+significantdifferencewas observedintherecoveryof
+codeine,C6GandNCG betweenEM andPM (Table2).
+Therenalclearanceofcodeinedidnotdiffersignificantly
+betweenEM andPM.
+Theresultsofthesingledosestudywereconfirmedin
+anextendedstudywithchronicdosing.Thesedataare
+presentedinTables3and4.
+Threeofthe14volunteersexperiencedslightside
+effectsincludingtiredness(oneEM andtwoPM)and
+headache(onePM)aftersingledose,andfiveofsix
+subjectsreportedtiredness(twoEM andtwoPM),
+dizziness(twoEM)nausea(oneEM andonePM)or
+headache(onePM)aftermultipledoses.
+Discussion
+Theresultsindicatesignificantinterindividualdiffer-
+encesinthecapacitytoformmorphinefromcodeine.
+IndividualswhowerePM phenotypesfordebrisoquine
+hydroxylationhadveryloworundetectableconcen-
+trationsoftheactivecompoundsM,M6GandNM.
+No majoralterationofcodeinepharmacokinetics
+occurredduringmultipledoseadministration,inaccord
+withthefindingsofothers(Guayetal.,1987).With
+regardtotheaccumulationofM afterchronicdosing,
+contradictoryresultshavebeenreported(Guayetal.,
+
+Codeinemetabolismanddebrisoquinephenotype639
+00 N0 b
+Cl Cl-)Cl
++l+1+1+1+1+1+1+1 t "ItO l
+*4 m011.000 00
+ 0000Cr-W)0000It
+'-en ONCl~0n e'vt+I+I+I+I+I+I+I+I
+/ 00 '- ON
+m00 0 r_
+ bN00 m00 l'
+ C)--oo *-4O W)o 00bq
+00N r ON0l
+,- -/t IN
+ )+1 +1+1+1+1+1+1
+r-8 tn,r oll- C)r-tn 0 Cooo00c'"C
+Cl O NClON te,,
+00 r,N0 00 N0C
+r.0-C- Cl4 CN0l 00ON
+ Cl Ci/N0
+C0004CDN00kn00
+ 66o ,so C' t t, Cl
+ +I+ +I+I+I+I+I+I
+ .',I /O Nv00
+- C')C')Cl0 -rNo
+90 N-OCl lC, 0
++l+l+l+I+l+l+l+l
+0ZnC)00 N VI)VI)0
+Cu ON '-tcfn00N0-C)NVI)N2
+C++I+I+I+ +l+I+I+ONlr- \IC "cl 00'ICN-
+O£NN'
+L 00 C. N -4r-0 C'nW)I/ I/N IN~0cl
+ ONC~00
+co enS
+ C' CO ulClC'(4
+U l)+ +I+I+I+I+I+l+
+') 00000 \C 1- r-4N
+- Nll~0)00'I"'"Cl
+o t.o
+ Z\Cu U
+ uu 's zS
+11
+CZ
+CZS.C
+0
+CO
+C.)
+CZ
+0
+0
+C.
+0
+to
+C)
+CZ
+0
+"0
+0
+ut
+"0
+C.)
+CZ~~~~~~~~~~~~C
+"0CO_O
+Cl
+c.)
+COU,
+I-
+C.
+.0
+CO
+c.)
+S U,
+"0CO
+C.)
+CO
+C._
+~~~C.)~ ~ ~ ~ ~ .
+0
+c.)
+ .= ~~~~~~~~~~~~CO
+~CO
+O.C 'I.
+ 0,=t~~~~~~~~~~~~4
+V*Cu
+- n(4)- CfNCC)O C)C
+-X+I+I+I+I+IZ Z Z
+00tr N 00
++1+1+1+1+1Z Z Z
+00tCN 00
+ OD
+00660o 00 0
+e'n "-4 "-
+rClr0I/"I/ZZZ +I+I+I+I+I
+I 1 8Wour tnZ Z Z00 "ClcON e-eCl-
+Cl+1+1+1 +1+1 z
+ 00 Cl~0)~ "-t
+00 r 00N 'I
+enen 000 N
+ ++I+I+I +IZ Z Z0000 00-1 0
+ . . . I/
+en OItO
+ +I+I+I +I+IZ Z Z
+00 C O0 00 m ON,CO
+c'c'00en 0%c
+ ++ + + +IZ Z Z
+ ..
+cn)+l1+l+l+1+IZ Z Z
+0000 N-Cl4(')
+X- o- - Cl 1-r
+\,o-,4,c"-,+l+1+1+1+1Z Z Z \ON* c * \0I t o)C,No)
+0ON o N C
+U +l+I+I+I +I Z
+ON 00\0-cn c'\)* :t
+ern
+.)
+'IO0 00 0
+U0'UICU enZ£,Cu u Z Z ,:,zSZ >
+II
++1
+C.CZ
+CZ)
+.4
+CZ
+0
+0
+CZ)
+C-
+0
+C.)
+0
+"0
+0X
+"0C.
+C.)
+C.)
+CO
+C.)
+c.)
+c.)cO
+"0
+0sC.)
+ .O
+.. .gU, ,X~CA
+C.- C)
+C) = U,
+-C -O
+O ,=11
+V; nzCA,, Z
+,£
+,Z
+4-
+640 Q.Y.Yueetal.
+1987;Quidingetal.,1986).We foundasignificant
+increaseintheCmaxofC6GandNCG (inPM,Table4)
+duringmultiple-doseadministration.However,noin-
+creasewasobservedforothermetabolitesofcodeine.
+Itiscommonlycitedthatapproximately10%ofan
+oraldoseofcodeineisrecoveredinurineasfreeand
+conjugatedM (Goodman&Gilman,1985).Thesefigures
+arebasedprimarilyonresultsobtainedusingradio-
+immunoassays(Findlayetal.,1977,1978;Rogersetal.,
+1982).Thecorrespondingfiguresinourstudywere6%
+inEM andlessthan0.4%inPM.M accountedforless
+than0.2%ofthedoseintheEM andwasessentially
+absentinthePM.The% relativeplasmaAUC ofM to
+codeinevariedfrom0.19and4.5%inEM andfrom0
+and0.13%inPM.Theseresultsareinagreementwith
+earlierdataobtainedbyaGC-MSmethodwithvalues
+rangingfrom0and4.4%in12volunteersafteroral
+dosesof60mgatsteady-state(Quidingetal.,1986).The
+meanplasmaCmaxvaluesofM were8.4nmol1-1inEM
+andlessthan2nmol1-1inPM,whichcomparewitha
+reportedvalueof3.5ngml-'(9.3nmoll-1)(Quidinget
+al.,1986).Themeanminimumeffectiveplasmacon-
+centrationofM forthereliefofpaininpatientsafter
+abdominalsurgeryhasbeenestimatedtobe16ngml-'
+(42.7nmoll-1)(Dahlstrometal.,1982).Considering
+theverylowplasmaconcentrationofM detectedatthe
+usualdosesofcodeineusedinthetreatmentofpainitis
+unlikelythatthismetabolitecontributesmuchtothe
+analgesiceffectofcodeineinman.
+M6Gisanotheractivemetaboliteofcodeineformed
+byO-demethylationtoM andfurtherglucuronidationat
+the6-position.Theanalgesicpotencyofthismetabolite
+hasbeenrecognizedformorethanadecade(Shimomura
+etal.,1971;Yoshimuraetal.,1973),butitspotential
+clinicalimportancewithrespecttoanalgesicactionhas
+onlybeenappreciatedrecently(Handetal.,1987;Joelet
+al.,1985;Osborneetal.,1988).Thus,M6Ghasbeen
+showntohaveananalgesiceffectapproximatelytwice
+thatofM whengivensubcutaneouslyinmice.However,
+wheninjectedeitherintracerebroventricularlyorintra-
+thecally,M6Gwasapproximately90-and650-foldmore
+potentananalgesicthanM,respectively(Pauletal.,
+1989).ThegreaterpotencyofM6Ghasalsobeenreported
+inrats(Abbott&Palmour,1988;Sullivanetal.,1989).
+TheincreaseddegreeanddurationofeffectofM in
+patientswithrenaldysfunctionhasfocusedattentionon
+theactivemetabolitesofM (Hasselstrometal.,1989;
+Osborneetal.,1986;Sawe,1986).Thei.v.administration
+of0.5-1mg70kg-'M6Gtocancerpatientsresultedin
+analgesicactivity,andithasbeensuggestedthatmostof
+theanalgesiceffectoccurringafterM treatmentisdueto
+thismetabolite(Osborneetal.,1988,1990).However,
+M6G isawatersolublecompoundanditsmovement
+throughthebloodbrainbarriermaybelimited.Inthe
+presentstudy,theAUC ofM6G wasalmostsixtimes
+higherthanthatofM aftercodeineadministration,
+whichisinaccordancewiththereportedmeanM6Gto
+M AUC ratioafteroralM (Osborneetal.,1990;Saweet
+al.,1985).Inconjunctionwiththedemonstrationofthe
+pharmacologicalactivityofM6G,thefindingsofthe
+presentstudysuggestthatM6Gplaysamoreimportant
+rolethanM intheanalgesiceffectofcodeine.
+NM whichisformedfromcodeinebybothN and0-
+demethylationalsohasanalgesiceffect(Lasagna& de
+Kornfeld,1958;Sullivanetal.,1989).NM wasequipotent
+withM afterintrathecalinjectionintorats(Sullivanet
+al.,1989).Whengiventorelievepostoperativepainin
+man,NM wasapproximatelyone-fourthaspotentasM
+(Lasagna&deKornfeld,1958).Inviewofthealmost10-
+foldhigherAUCofNM comparedtothatofM observed
+inthisstudy,NM mightalsomakeasignificantcontribu-
+tiontoanalgesiaafteradministrationofcodeine.
+ThevaluesofCmax,tmax,AUC andt½/2ofcodeine
+observedinthisstudyweresimilartothosereportedby
+others(Findlayetal.,1977,1978;Quidingetal.,1986)
+andtherewerenosignificantdifferencesbetweenEM
+andPM.TheAUC andurinaryrecoveryofC6Gwere
+alsosimilarinEM andPM.Asfarasweknow,C6Ghas
+notbeenshowntohaveanyanalgesiceffect.However,
+PMhadasignificantlyhigherAUC andurinaryrecovery
+ofNCcomparedtoEM whichisinterestingsinceithas
+beenreportedthatNChasanalgesicactivity(Miller&
+Anderson,1954).Thesedifferencesconfirmobservations
+madeinapopulationstudyinwhichurinesamplesfrom
+severalhundredhealthyvolunteerswereanalysed(Yue
+etal.,1989b).Thedifferenceintheconcentrationsof
+NCwaslessthantwo-foldbetweenthetwophenotypes
+andtheefficacyofNC appearsnottobegreaterthan
+thatofcodeine(Miller&Anderson,1954).Therefore,
+higherconcentrationsofNCwouldnotbeexpectedto
+compensateforthedifferencesbetweenEM andPMin
+theformationofO-demethylatedmetabolites.
+Theclinicalsignificanceofdebrisoquineoxidation
+polymorphismhasbeenreviewed(Br0sen& Gram,
+1989;Sjoqvist,1989a,1989b).Ingeneralitisimportant
+onlywhenthekineticsofthedrugaresignificantlyde-
+pendentonthespecificisoenzymecytochromeP4501ID6.
+Codeinemightbeanexceptiontothis.Although0-
+demethylationofcodeineisonlyaminormetabolic
+routeandthekineticsoftheparentdrugarenotsignif-
+icantlyinfluencedbythispathway,itcouldbeofclinical
+importancebecauseoftheactivityofthemetabolites
+associatedwiththispathway.Ithasbeensuggestedthat
+codeineisineffectiveinPM,butonlyonePMvolunteer
+wasincludedinthestudy(Desmeulesetal.,1989).A
+moredetailedinvestigationoftheanalgesiceffectof
+codeineisindicatedusingalargersamplesize.
+Inconclusion,CaucasianswhoarePMofdebrisoquine
+haveveryloworundetectableplasmaconcentrationsof
+the0-demethylatedmetabolitemorphine,aswellaslow
+concentrationsofthetwootherimportantactivemet-
+abolitesmorphine-6-glucuronideandnormorphine.The
+plasmaclearanceofcodeineissimilarinCaucasianEM
+andPM.
+ThisworkwassupportedbytheSwedishResearchCouncil
+(3902)andtheSwedishCancerSociety(1910-B88-O1V).SamplesofcodeinemetaboliteswerekindlyprovidedbyNation-
+alInstituteofDrugAbuse,USA.
+Codeinemetabolismanddebrisoquinephenotype641
+References
+Abbott,F.V.& Palmour,R.M.(1988).Morphine-6-glucu-
+ronide:analgesiceffectsandreceptorbindingprofilein
+rats.LifeSci.,43,1685-1695.
+Bechtel,W.D.& Sinterhauf,K.(1978).Plasmaleveland
+renalexcretionof[3H]codeinephosphateinmanandinthe
+dog.Arzneim.-Forsch.,28,308-311.
+Bodd,E.,Beylich,K.M.,Christophersen,A.S.&Morland,
+J.(1987).Oraladministrationofcodeineinthepresenceof
+ethanol:apharmacokineticstudyinman.Pharmac.Tox.,
+61,297-300.
+Br0sen,K.&Gram,L.F.(1989).Clinicalsignificanceofthe
+sparteine/debrisoquineoxidationpolymorphism.Eur.J.
+clin.Pharmac.,36,537-547.
+Chen,Z.R.,Somogyi,A.A.& Bochner,F.(1988).Poly-
+morphicO-demethylationofcodeine.Lancet,ii,914-915.
+Dahlstrom,B.,Tamsen,A.,Paalzow,L.&Hartvig,P.(1982).
+Patient-controlledanalgesictherapy,partIV:Pharmaco-
+kineticsandanalgesicplasmaconcentrationsofmorphine.
+Clin.Pharmacokin.,7,266-279.
+Dayer,P.,Desmeules,J.,Leemann,T.&Stribemi,R.(1988).
+Bioactivationofthenarcoticdrugcodeineinhumanliveris
+mediatedbythepolymorphicmonooxygenasecatalyzing
+debrisoquine4-hydroxylation(cytochromeP-450dbl/bufI).
+Biochem.Biophys.Res.Commun.,152,411-416.
+Desmeules,J.,Dayer,P.,Gascon,M.P.& Magistris,M.
+(1989).Impactofgeneticandenvironmentalfactorson
+codeineanalgesia.Clin.Pharmac.Ther.,45,122.
+Evans,D.A.,Mahgoub,A.,Sloan,T.P.,Idle,J.R.&Smith,
+R.L.(1980).Afamilyandpopulationstudyofthegenetic
+polymorphismofdebrisoquineoxidationinawhiteBritish
+population.J.med.Genet.,17,102-105.
+Findlay,J.W. A.,Butz,R.F.& Welch,R.M.(1977).
+Codeinekineticsasdeterminedbyradioimmunoassay.Clin.
+Pharmac.Ther.,22,439-446.
+Findlay,J.W.A.,Jones,E.C.,Butz,R.F.&Welch,R.M.
+(1978).Plasmacodeineandmorphineconcentrationsafter
+therapeuticoraldosesofcodeine-containinganalgesics.
+Clin.Pharmac.Ther.,24,60-68.
+Goodman,L.J.& Gilman,A.(1985).Thepharmacological
+basisoftherapeutics,TheodoreW.Rall,7thed.,p.506.
+NewYork:Macmillan.
+Guay,D.R.P.,Awni,W.M.,Halstenson,C.E.,Findlay,
+J.W.A.,Opsahl,J.A.,Abraham,P.A.,Jones,E.C.&
+Matzke,G.R.(1987).Pharmacokineticsofcodeineafter
+single-andmultiple-oral-doseadministrationtonormal
+volunteers.J.clin.Pharmac.,27,983-987.
+Guay,D.R.P.,Awni,W.M.,Findlay,J.W.A.,Halstenson,
+C.E.,Abraham,P.A.,Opsahl,J.A.,Jones,E.C.&
+Matzke,G.R.(1988).Pharmacokineticsandpharmaco-
+dynamicsofcodeineinend-stagerenaldisease.Clin.Phar-
+mac.Ther.,43,63-71.
+Hand,C.W.,Blunnie,W.P.,Claffey,L.P.,McShane,A.J.,
+McQuay,H.J.&Moore,R.A.(1987).Potentialanalgesic
+contributionfrommorphine-6-glucuronideinCSF.Lancet,
+ii,1207-1208.
+Hasselstrom,J.,Berg,U.,Lofgren,A.& Sawe,J.(1989).
+Longlastingrespiratorydepressioninducedbymorphine-
+6-glucuronide?Br.J.clin.Pharmac.,27,515-518.
+Joel,S.P.,Osborne,R.J.,Nixon,N.S.& Slevin,M.L.
+(1985).Morphine-6-glucuronide,animportantmetabolite.
+Lancet,i,1099-1100.
+Lasagna,L.&DeKornfeld,T.J.(1958).Analgesicpotencyof
+normorphineinpatientswithpostoperativepain.J.Phar-
+mac.,124,260-263.
+Lennard,M.S.,Silas,J.H.,Smith,A.J.& Tucker,G.T.
+(1977).Determinationofdebrisoquineandits4-hydroxy
+metaboliteinbiologicalfluidsbygaschromatographywith
+flame-ionizationandnitrogen-selectivedetection.J.
+Chromatogr.,133,161-166.
+Mahgoub,A.,Idle,J.R.,Dring,L.G.,Lancaster,R.&
+Smith,R.L.(1977).Polymorphichydroxylationofdebriso-
+quineinman.Lancet,ii,584-586.
+Miller,J.W.& Anderson,H.H.(1954).TheeffectofN-
+demethylationoncertainpharmacologicactionsofmor-
+phine,codeineandmeperidineinthemouse.J.Pharmac.,
+112,191-196.
+Osborne,R.J.,Joel,S.P.&Slevin,M.L.(1986).Morphine
+intoxicationinrenalfailure:theroleofmorphine-6-glucu-
+ronide.Br.med.J.,282,1548-1549.
+Osborne,R.J.,Joel,S.P.,Trew,D.& Slevin,M.(1988).
+Analgesicactivityofmorphine-6-glucuronide.Lancet,i,
+828.
+Osborne,R.,Joel,S.,Trew,D.&Slevin,M.(1990).Morphine
+andmetabolitebehaviorafterdifferentroutesofmorphine
+administration:demonstrationoftheimportanceofthe
+activemetabolitemorphine-6-glucuronide.Clin.Pharmac.
+Ther.,47,12-19.
+Paul,D.,Standifer,K.M.,Inturrisi,C.E.&Pasternak,G.W.
+(1989).Pharmacologicalcharacterizationofmorphine-6p-glucuronide,averypotentmorphinemetabolite.J.Pharmac.
+exp.Ther.,251,477-483.
+Quiding,H.,Anderson,P.,Bondesson,U.,Boreus,L.0.&
+Hynning,P.A.(1986).Plasmaconcentrationsofcodeine
+anditsmetabolite,morphine,aftersingleandrepeatedoral
+administration.Eur.J.clin.Pharmac.,30,673-677.
+Rogers,J.F.,Findlay,J.W.A.,Hull,J.H.,Butz,R.F.,
+Jones,E.C.,Bustrack,J.A.& Welch,R.M.(1982).
+Codeinedispositioninsmokersandnonsmokers.Clin.
+Pharmac.Ther.,32,983-987.
+Sanfilippo,G.(1948).Contributosperimentaleall'ipotesi
+dellasmetilazionedellacodeinenell'organismo.I.Influenze
+delladosesull'assuefazioneallacodeine.II.Assuefazione
+allacodeineattenutaconsomministrazioneprolungatadi
+morfina.Boll.Soc.Ital.Biol.Sper.,24,723-726.
+Sawe,J.(1986).High-dosemorphineandmethadoneincancer
+patients.Clinicalpharmacokineticconsiderationoforal
+treatment.Clin.Pharmacokin.,11,87-106.
+Sawe,J.,Kager,L.,Svensson,J.0.&Rane,A.(1985).Oral
+morphineincancerpatients:invivokineticsandinvitro
+hepaticglucuronidation.Br.J.clin.Pharmac.,19,495-
+501.
+Shimomura,K.,Kamata,O.,Ueki,S.,Ida,S.,Oguri,K.,
+Yoshimura,H.&Tsukamoto,H.(1971).Analgesiceffect
+ofmorphineglucuronides.TohokuJ.exp.Med.,105,45-
+52.
+Sjoqvist,F.(1989a).Polymorphicdrugoxidation- clinical
+implications.Rev.Pharmac.clin.Exp.,6,189-191.
+Sjoqvist,F.(1989b).Slowdrughydroxylation- implications
+forpatientmanagementanddrugutilization.InXenobiotic
+metabolismanddisposition,ed.Kato,R.,Estabrook,R.
+W. & Cayen,M.N.,pp476-482.London:Taylor&
+Francis.
+Steiner,E.,Bertilsson,L.,Sawe,J.,Bertling,I.&Sjoqvist,F.
+(1988).Polymorphicdebrisoquinehydroxylationin757
+Swedishsubjects.Clin.Pharmac.Ther.,44,431-435.
+Sullivan,A.F.,McQuay,H.J.,Bailey,D.& Dickenson,A.
+H.(1989).Thespinalantinociceptiveactionsofmorphine
+metabolites,morphine-6p-glucuronideandnormorphine
+intherat.BrianRes.,482,219-224.
+Svensson,J.0.(1986).Determinationofmorphine,morphine-
+6-glucuronideandnormorphineinplasmaandurinewith
+high-performanceliquidchromatographyandelectro-
+chemicaldetection.I.Chromatogr.,375,174-178.
+Yoshimura,H.,Ida,S.,Oguri,K.& Tsukamoto,H.(1973).
+642 Q.Y.Yue.,etal.
+Biochemicalbasisforanalgesicactivityofmorphine-6,-
+glucuronide-I:Penetrationofmorphine-6-glucuronidein
+thebrainofrats.Biochem.Pharmac.,22,1423-1430.
+Yue,Q.Y.,Sawe,J.,Svensson,J.0.& Sjoqvist,F.(1988).
+InterindividualandinterethnicdifferencesintheO-de-
+methylationandglucuronidationofcodeine- observations
+inChineseandSwedishvolunteers.5thSoutheastAsianand
+WesternPacificRegionalMeetingofPharmacologists.
+Beijing,China,July1988.
+Yue,Q.Y.,Svensson,J.O.,Alm,C.,Sjoqvist,F.&Sawe,J.
+(1989a).Interindividualandinterethnicdifferencesinthe
+demethylationandglucuronidationofcodeine.Br.J.clin.
+Pharmac.,28,629-637.
+Yue,Q.Y.,Svensson,J.O.,Alm,C.,Sjoqvist,F.&Sawe,J.
+(1989b).CodeineO-demethylationco-segregateswithpoly-
+morphicdebrisoquinehydroxylation.Br.J.clin.Pharmac.,
+28,639-645.
+(Received24July1990,
+accepted6December1990)

papers/PKDB00119.md

@@ -0,0 +1,16 @@
+# Chronopharmacokinetics of paracetamol in normal subjects.
+
+J Malan, J Moncrieff, E Bosch
+
+*British journal of clinical pharmacology* (1985)
+
+PMID: 4027126
+DOI: 10.1111/j.1365-2125.1985.tb02726.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+The chronopharmacokinetics of paracetamol was studied in six male volunteers. Serum concentrations of paracetamol were determined after a single oral dose of 1 g, on three occasions, spaced at least 1 week apart. Plasma drug concentration vs time curves were obtained after dosage at 08.00 h (Day 1), 14.00 h (Day 2) and 20.00 h (Day 3), under standardized conditions. Pharmacokinetic parameters compared were t1/2,alpha, t1/2,Z, tmax, Cmax and AUCpo. No statistically significant differences were found.

papers/PKDB00119.pdf

@@ -0,0 +1,3 @@
+version https://git-lfs.github.com/spec/v1
+oid sha256:6ea12313561f17675f9b36386e7a31e9495fb72bc2d6b92863cac2b45fc53e1c
+size 258031

papers/PKDB00119.txt

@@ -0,0 +1,173 @@
+Br.J.clin.Pharmac.(1985),19,843-845
+Chronopharmacokineticsofparacetamolinnormalsubjects
+J.MALAN,J.MONCRIEFF& E.BOSCH
+DepartmentofPharmacology,UniversityofPretoria,Pretoria,RepublicofSouthAfrica
+Thechronopharmacokineticsofparacetamolwas studiedinsixmalevolunteers.Serum
+concentrationsofparacetamolwere determinedafterasingleoraldoseof1g,on three
+occasions,spacedatleast1weekapart.Plasmadrugconcentrationvstimecurveswere
+obtainedafterdosageat08.00h(Day1),14.00h(Day2)and20.00h(Day3),under
+standardizedconditions.Pharmacokineticparameterscomparedwere tl,t1/2,ztma
+CmaxandAUCpO.Nostatisticallysignificantdifferenceswerefound.
+Keywordsparacetamolpharmacokineticschronopharmacology
+Introduction
+Circadianrhythmicchangesinthepharmaco-
+kineticsofseveraldrugshavebeendocumented
+andreviewed(Reinberg&Smolensky,1982).
+Inthecaseofparacetamol,ithasbeennoted
+thattheeliminationhalf-lifewasslightly(15%),
+butsignificantly(P< 0.025)longerinhealthy
+malesat06.00hthanat14.00h(Shively&
+Vesell,1975).
+We decidedtoinvestigateandcompare
+possibledifferencesinpharmacokineticpara-
+meters(t2,,,t½,z,tmaxCmmaandAUCpO)after
+asingledoseofparacetamol,whentakenat
+08.00h,14.00hand20.00h.
+Methods
+Sixhealthynon-smokingadultmalevolunteers
+participatedinthestudy.An opencross-over
+trialdesignwasused,i.e.eachvolunteerserved
+ashisowncontrol.Writteninformedconsent
+wasobtainedandthestudyapprovedbythe
+localEthicsCommittee.
+Onthreeoccasions,spacedatleast1week
+apart,thesubjectstook1gofparacetamol(2x
+500mgtablets:Panadolg)asasingledoseper
+os,with250mltapwater.Onthefirsttrialday,
+medicationwastakenat08.00h,onthesecond
+at14.00handonthethird,at20.00h.
+Thevolunteerswerefastingforatleast8h
+whendosingtookplace.A standardizedmeal
+wasingested2haftermedication.Forthesefirst
+843
+2hofeachstudy,thesubjectsweresupine.No
+othermedicationwaspermittedfortheduration
+oftheproject.Bloodsamplesweredrawnviaan
+indwellingintravenouscannula,beforeandat
+thefollowingintervalsaftermedication:0.25,
+0.5,0.75,1,1.5,2,2.5,3,3.5,4,6and8h.
+Thesampleswereassayedbyh.p.l.c.usinga
+rapidmicromethoddevelopedinthedepart-
+ment,utilizingreversephaseseparationand
+u.v./VISspectrophotometricdetectionat
+247nm,withaminophyllineasinternalstandard.
+Internalstandardwasaddedto100ILserum
+inacentrifugetubetogiveaconcentrationof20
+t.g/ml.Theproteinwasthenprecipitatedwith
+10%perchloricacidand,aftershaking,thetube
+wasspunat3000rev/minfor3minand100,ulof
+theclearsupernatantwasinjectedontotheC18
+reversephasecolumnandelutedwith6%ace-
+tonitrileinpH3phosphatebufferataflowrate
+of2.5mlminandacolumntemperatureof370C.
+Thedrugwasdetectedat247nmandquantified
+fromthestandardscurveonthebasisofpeak
+heightratio.Thedetectionlimitwas0.1p.g/mlandthedeviationwas±0.1atthe5,ug/mllevel.
+Theresponsewaslinearfrom0.5,ug/ml-50,ug/
+mlwithacorrelationcoefficientof1.000.
+Datawereprocessedby'CSTRIP',acom-
+puterprogramforobtaininginitialpoly-
+exponentialparameterestimates(Sedman&
+Wagner,1976).TheFriedmantestwasusedtodetermine
+statisticallysignificantdifferences.AP-valueof
+c0.05wasregardedasindicativeofsignificance.
+844 J.Malan,J.Moncrieff&E.Bosch
+Results
+Themeanvalues(n=6)ofthefollowingphar-
+macokineticparametersaresummarizedin
+Table1andillustratedgraphicallyinFigure1:
+t/2,a7,t%2tmax,CmaxandAUCpo
+Table1 Results(meanvaluesands.d.)ofpharmaco-
+kineticdataevaluated
+Mean
+Parameter Day (n=6) s.d.
+t,,,(h) 1 0.2 0.1
+2 0.2 0.0
+3 0.2 0.1
+t½,2z(h) 1 2.4 0.4
+2 2.3 0.5
+3 2.5 0.2
+tmax(h) 1 0.8 0.2
+2 0.9 0.3
+3 1.0 0.1
+Cmax 1 9.0 2.8
+(Fig/ml) 2 9.4 3.4
+3 8.7 1.6
+AUCpO 1 33.0 10.4
+(mgml-h) 2 34.8 14.9
+3 35.2 8.3
+Day1= medicationgivenat08.00h,
+Day2= medicationgivenat14.00hand
+Day3= medicationgivenat20.00h
+Ithasbeenestablishedthattherearecircadian
+changesofdrugdispositioninman (Reinberg&
+Smolensky,1982).Thesechronopharmaco-
+kineticdifferencesmay beoftherapeuticimpor-
+tanceinsome cases,e.g.forindomethacin
+(Clenchetal.,1981;Guissouetal.,1983)and
+theophylline(Leskoetal.,1980).
+Itwas previouslyreportedthattheterminal
+eliminationhalf-life(to/2z)Ofparacetamolwas
+significantlylongerinnormalvolunteerswhen
+givenat06.00hthanat14.00h(131.18minat
+06.00h;114 9.8minat14.00h;decreaseequal
+to± 15%,P< 0.025)(Shively&Vesell,1975).
+Thiswaspresumedtobeduetoachangeinthe
+volumeofdistribution.Ithasalsobeenclaimed
+thatparacetamolabsorptionwasfivetimesmore
+rapidafteran overnightfastthanaftercon-
+comitantingestionofahighcarbohydratebreak-
+fast(McGilveray& Mattok,1972).
+Ourstudywasdoneunderrigidlycontrolled
+andstandardizedconditions.Itisclearthatno
+statisticallysignificantdifferenceswere found
+betweenthepharmacokineticparametersstudied,
+andthattimeofdosingdidnotseem tocause
+influentialchangesintheabsorptionanddis-
+positionpatternofparacetamol.
+10
+8
+ | N
+E
+CD
+:u
+ 6
+E
+co
+C/)
+2
+0 1 2 3 4 5 6 7 8
+Time(h)
+Figure1 Meanserumconcentrationsofparacetamolafteradministrationat08.00h(v),14.00h(0)and
+20.00h(-).
+Discussion
+Shortreport845
+References
+Clench,J.,Reinberg,A.,Dziewanowska,Z.,Ghata,
+J.& Smolensky,M.(1981).Circadianchangesin
+thebioavailabilityandeffectsofindomethacinin
+healthysubjects.Eur.J.clin.Pharmac.,20,359-
+369.
+Guissou,P.,Cuisinaud,G.,Llorca,G.,Lejeune,E.&
+Sassard,J.(1983).Chronopharmacokineticstudy
+ofaprolongedreleaseformofindomethacin.Eur.
+J.clin.Pharmac.,24,667-670.
+Lesko,L.J.,Brousseau,D.,Canada,A.T.& East-
+wood,G.(1980).Temporalvariationsintrough
+serumtheophyllineconcentrationsatsteadystate.
+J.pharm.Sci.,69,358-359.
+McGilveray,I.J.& Mattok,G.L.(1972).Some
+factorsaffectingtheabsorptionofparacetamol.J.
+Pharm.Pharmac.,24,615-619.
+Reinberg,A.& Smolensky,M.H.(1982).Circadian
+changesofdrugdispositioninman.Clin.Phar-
+macokin.,7,401-420.
+Sedman,A.J.& Wagner,J.G.(1976).CSTRIP,a
+FortranIVcomputerprogramforobtainingInitial
+PolyexponentialParameterEstimates.J.pharm.
+Sci.,65,1007-1010.
+Shively,C.A.&Vesell,E.S.(1975).Temporalvaria-
+tionsinacetaminophenandphenacetinhalf-lifein
+man.Clin.Pharmac.Ther.,18,413-424.
+(ReceivedOctober24,1984,
+acceptedFebruary5,1985)

papers/PKDB00121.md

@@ -0,0 +1,16 @@
+# Effect of excipients on acetaminophen metabolism and its implications for prevention of liver injury.
+
+Michael Ganetsky, Mark Böhlke, Luis Pereira, David Williams, Barbara LeDuc, Shiva Guatam, Steven D Salhanick
+
+*Journal of clinical pharmacology* (2013)
+
+PMID: 23436315
+DOI: 10.1002/jcph.24
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen, primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15 mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protective effect of this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially be developed if co-formulated with a CYP2E1 inhibitor.

papers/PKDB00121.pdf

@@ -0,0 +1,3 @@
+version https://git-lfs.github.com/spec/v1
+oid sha256:1b6d50126c899b81c1fc11a782ef9d26e90e51b3e0056abc2c2ee57463977515
+size 440851

papers/PKDB00121.txt

@@ -0,0 +1,567 @@
+Effect of Excipients on Acetaminophen
+Metabolism and Its Implications
+for Prevention of Liver Injury
+Michael Ganetsky, MD 1a, Mark Böhlke, PhD 2b, Luis Pereira, PhD 3c,
+David Williams, PhD 4d, Barbara LeDuc, PhD 2e, Shiva Guatam, PhD 1f, and
+Steven D. Salhanick, MD 5a
+Abstract
+Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen,
+primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular
+injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single ‐
+blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15 mg/kg dose of liquid versus solid
+preparations of acetaminophen. Measured AUC’s for the CYP2E1 metabolites were 16–17% lower and extrapolated AUC’s were 25–28% lower in the
+liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metaboliteswere
+equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive
+antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protectiveeffect of
+this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially
+be developed if co ‐formulated with a CYP2E1 inhibitor.
+Keywords
+acetaminophen, CYP2E1, liver failure, propylene glycol
+Acetaminophen (APAP) poisoning is the leading cause of
+acute hepatic failure in the United States (U.S.) and
+Europe.1,2 An estimated 33 520 patients are hospitalized
+in the U.S. following APAP poisoning annually. 3 APAP
+poisoning is responsible for half of the liver transplants
+that follow drug‐induced liver failure in the U.S.4 Cases of
+hepatic failure due to APAP toxicity continue to rise. 1,5
+Hepatocellular injury is initiated by the metabolism of
+excess amounts of APAP. Most of the APAP ingested is
+metabolized by direct phase II conjugation with sulfate
+and glucuronide. Toxicity is due to an increase in the
+amount of APAP undergoing reductive metabolism,
+primarily via cytochrome P450 2E1 (CYP2E1), and can
+occur following intentional overdose or during chronic
+supratherapeutic dosing.
+6 Most clinicians and investiga-
+tors believe that hepatocellular damage is mediated via
+N‐acetyl‐p‐benzoquinone imine (NAPQI), the principal
+reactive metabolite produced by CYP2E1 (Figure 1A).
+Recent investigation into the epidemiology of APAP
+poisoning reveals that cough and cold preparations, which
+are often liquid formulations, are underrepresented among
+APAP formulations causing toxicity.
+5 Additionally,
+children appear less susceptible to APAP ‐induced liver
+injury than adults. 7 Suggested mechanisms include
+increased sulfonation capacity, relatively larger liver
+The Journal of Clinical Pharmacology
+53(4) 413 –420
+©The Author(s) 2013
+DOI: 10.1002/jcph.24
+1Department of Emergency Medicine, Beth Israel Deaconess Medical
+Center, Harvard Medical School, Boston, MA, USA
+2Massachusetts College of Pharmacy and Health Sciences, Boston, MA,
+USA
+3Quantitative Clinical Pharmacology and Pharmacokinetics Laboratory,
+Department of Anesthesia, Children ’s Hospital Boston, Harvard
+Medical School, Boston, MA, USA
+4Professor Emeritus of Chemistry, Massachusetts College of Pharmacy
+and Health Sciences, Boston, MA, USA
+5Department of Emergency Medicine, Beth Israel Deaconess Medical
+Center, Harvard Medical School, Boston, MA, USA
+Submitted for publication 10 May 2012; accepted 9 August 2012.
+Corresponding Author:
+Steven D. Salhanick, MD, Assistant Professor, Harvard Medical School,
+Department of Emergency Medicine, Beth Israel Deaconess Medical
+Center, One Deaconess Road, WCC ‐2, Boston, MA 02215
+Email: sshalni@bidmc.harvard.edu
+Trial registration: Effect on Acetaminophen Metabolism by Liquid
+Formulations NCT01246713.
+aAssistant Professor.
+bSenior Scientist.
+cDirector; Instructor of Anesthesia.
+dProfessor Emeritus of Chemistry
+eAssociate Professor of Pharmacology.
+fAssociate Professor.
+Pharmacokinetics
+size as well as increased relative supply of glutathione.8–12
+However, children tend to ingest liquid preparations
+instead of solid suggesting it may be it is the preparation
+and not the unique physiology of children that could
+explain this effect.
+Liquid APAP preparations contain propylene glycol
+(PG), a solubilizing agent used to dissolve APAP in
+aqueous solutions.
+13 In murine and in vitro models of
+acetaminophen toxicity, PG has been found to reduce
+hepatic injury via inhibition of CYP2E1.14,15 We therefore
+sought to investigate the difference in metabolism
+following ingestion of liquid versus solid APAP prepa-
+rations in adults to see if an excipient may be inhibiting
+reductive metabolism, which could potentially be
+protective.
+Methods
+Participants
+Subjects were recruited via internet advertisement.
+Eligibility criteria included age 18 –40 years, no daily
+medications and no chronic or acute medical conditions.
+Specific exclusion criteria were any history of liver
+disease, ingestion of two or more alcoholic beverages
+more than four times per week, or pregnancy.
+Study Protocol
+The protocol and all interventions were approved by the
+Institutional Review Board at the Beth Israel Deaconess
+Medical Center. We performed a single‐blinded crossover
+pharmacokinetic study at our institution’s clinical research
+center.
+Figure 1. Metabolism of acetaminophen. A: P450 metabolism results in NAPQI radical production, which binds and reduces levels of intracellular
+glutathione leading to decreased redox buffering capacity. NAPQI arylated proteins and initiates toxicity. APAP CYP minor metabolites include APA P‐
+glutathione, APAP‐cysteinate, and APAP‐mercapturate. B: The compartmental model for acetaminophen metabolism used for the pharmacokinetic analysis.
+414 The Journal of Clinical Pharmacology / Vol 53 No 4 (2013)
+Each subject had a screening visit to review medical
+history and obtain consent. Baseline testing included
+serum chemistries, renal function tests, liver function tests
+(Roche Hitachi Modular, Basel, Switzerland), complete
+blood counts (Sysmex XE2100, Kobe City, Hyogo
+Prefecture, Japan), and a urine pregnancy test.
+Subjects had two separate study visits at least 1 week
+apart to allow for full clearance of APAP metabolites.
+They were instructed not to take any APAP or ethanol for
+48 hours prior to each visit. Subjects were randomized to
+receive a standard commercially available tablet or liquid
+formulation of APAP on the first visit. The alternative
+preparation was given on the second visit. At presentation
+for each visit, plasma APAP concentrations were
+measured to con firm lack of use. Subjects underwent a
+1 hour fast, then received a 15 mg/kg oral dose of APAP.
+The liquid dose was always equivalent to the closest
+possible rounded‐down solid dose that could be adminis-
+tered with standard APAP tablets. Plasma samples were
+collected at 30 minutes, and at 1 hours, 2 hours, 4 hours,
+6 hours, and 8 hours after APAP administration. Subjects
+were provided a standard lunch.
+Blood samples were refrigerated for not more than
+24 hours and then plasma was separated by centrifugation.
+All samples were then stored at /C0 80°C.
+Quantitative Assays of Acetaminophen and Metabolites
+The authors (M.B., D.W.) performing the LC/MS/MS
+analysis were blinded to the formulation administered at
+each visit. Plasma samples were assayed for APAP,
+APAP‐glucuronide, APAP ‐sulfate (conjugative metabo-
+lites), APAP ‐cysteinate, and APAP ‐mecapturate (reduc-
+tive metabolites). Samples were prepared by diluting one
+volume of plasma with two volumes of acetonitrile,
+vortexing for 10 seconds, then placing the mixture on
+ice for 10 minutes. This was followed by centrifuging
+samples for 6 minutes at 14 000 rpm, diluting with the
+initial mobile phase, and centrifuging for an additional
+2 minutes before transferring final solutions into limited ‐
+volume (250 µL) autosampler vials for 5 µL injections
+into the HPLC system. Samples were analyzed with an
+Agilent 1100 HPLC system coupled to an AB/SCIEX API
+3000 mass spectrometer. Analytes were separated on a
+Kinetex C18 column (100 mm /C2 2.1 mm, 2.6 µm par-
+ticles, Phenomenex, Torrance, CA), using mobile phases
+of water (A) and acetonitrile (B), each containing 0.1%
+formic acid, with gradient elution as follows: 8% B from 0
+to 1.2 minutes, to 70% B at 6 minutes, to 85% B at
+7 minutes, to 95% B at 10 minutes, returned to 8% B at
+10.2 minutes, and equilibrated to 20 minutes before the
+next injection. Standards for calibration were prepared by
+spiking minimal volumes of concentrated solutions of
+each standard (1 mg/mL of APAP ‐cysteinate, APAP ‐
+glutathione and APAP ‐mercapturate and 10 mg/mL of
+APAP‐glucuronide, APAP ‐sulfate, and APAP) into
+plasma that was collected from a healthy volunteer taking
+no medications that had been screened to establish that
+these compounds were absent.
+Quantitative Assays of Propylene Glycol
+Plasma PG concentrations were measured at NMS Labs
+using a Hewlett Packard 5890 GC with FID detector.
+Samples from time points zero through 120 minutes from
+three subjects were assayed first. PG was detected in the
+30‐minute time point in all three, and in one subject at
+120 minutes. Given these initial results and since enteral
+absorption of PG is rapid, subsequently all of the
+30‐minute time point samples from all subjects were
+assayed. The limit of detection of this assay is 5.0 mg/dL.
+Pharmacokinetic and Statistical Evaluation
+Power analysis was based on the following assumptions:
+we expected approximately five to ten percent of the
+ingested APAP to undergo reductive metabolism.
+16–18
+Assuming a difference of 50% between groups, a
+calculated sample size of ten subjects would exceed the
+number needed to enroll with a power of at least 80%. To
+allow for attrition, we planned to enroll 15 subjects.
+Area under curve to the last time point (AUC t
+0) was
+calculated using the trapezoidal method and individual
+profiles were also fitted by nonlinear regression. Initial
+pharmacokinetic parameter estimates were determined for
+each subject by fitting the concentration data separately,
+then optimized by simultaneously fitting all data using
+NONMEM 7.2 software (ICON, Dublin, Ireland). AUC ’s
+extrapolated to in finity (AUC 1
+0 ) and formation rate
+constants for all metabolites (k s,k g,k c,k m) were thus
+calculated (based on the compartmental model in
+Figure 1B). Peak concentrations, AUC ’s, percent metab-
+olites and formation rate constants of liquid versus solid
+preparations were all compared with a paired ‐sample two‐
+tailed t‐test.
+Results
+A total of 15 subjects completed both study visits. The
+mean age of the subjects was 28 years, 10 (67%) subjects
+were male, and their mean weight was 82 kg (range 60 –
+128 kg). The mean acetaminophen dose administered was
+1 197 mg (range 825 –1 900 mg, median dose 1 150 mg)
+and 9 (60%) subjects were randomized to start with the
+liquid formulation.
+There was no statistically signi ficant difference in
+measured and modeled AUC ’s or peak concentrations for
+APAP and the phase ‐II metabolites (APAP ‐glucuronide
+and APAP ‐sulfate) following ingestion of solid versus
+liquid preparations (Table 1 and Figure 2A,B). There was
+a trend towards greater bioavailability of the liquid
+formulation, however this was not signi ficant (APAP
+AUC
+t
+0 54.5 µg hour/mL vs. 51.4 µg hour/mL, P ¼ .089).
+Ganetsky et al. 415
+Following ingestion of the liquid preparation (relative
+to the solid) there was 17% less measured APAP ‐
+cysteinate (AUC t
+0 2.411 µg hour/mL vs. 2.009 µg hour/
+mL, P ¼ .007), 25% less modeled APAP ‐cysteinate
+(AUC1
+0 5.699 µg hour/mL vs. 4.288 µg hour/mL, P ¼
+.007), 16% less measured APAP ‐mercapturate (AUC t
+0
+0.716 µg hour/mL vs. 0.602 µg hour/mL, P ¼ .006), and
+28% less modeled APAP ‐mercapturate (AUC1
+0 1.515 µg
+hour/mL vs. 1.096 µg hour/mL, P ¼ .005) in serum. The
+peak concentrations were also signi ficantly lower follow-
+ing liquid formulation ingestion for both APAP‐cysteinate
+and APAP ‐mercapturate (Table 1 and Figure 2C).
+The goodness of fit achieved in the nonlinear
+regressions of the metabolite measurements resulted in a
+range of coef ficients of correlation between 0.932 and
+0.986, standardized residuals with no detectable trends
+and mostly within /C0 3 and þ3, and predictive con fidence
+regions encompassing all observations with minimal over‐
+and under ‐prediction.
+There was no signi ficant difference in formation rate
+constants for APAP ‐cysteinate, APAP ‐mercapturate, or
+APAP‐sulfate (Figure 3) The formation rate constant for
+APAP‐glucuronide was signi ficantly greater for the solid
+as compared to liquid formulation (0.777 hour
+/C0 1 vs.
+0.622 hour /C0 1, P ¼ .015), however there was large
+overlap between the interquartile ranges.
+PG was detected in 9 out of 15 30 minutes samples
+obtained following ingestion of the liquid preparation, but
+in none of the samples in the solid group. The average PG
+concentration in these nine samples was 6.2 mg/dL and
+the maximum concentration was 9.1 mg/dL.
+Discussion
+APAP is bioactivated to NAPQI, the radical metabolite
+generally considered to be the necessary initiating step in
+APAP‐induced liver injury, primarily via CYP2E1.
+Intracellular glutathione is the major hepatocyte redox
+buffer; it binds NAPQI producing APAP ‐glutathione,
+which is subsequently metabolized to the cysteinate and
+mercapturate metabolites.
+19,20 We show a 16 –28%
+decrease in production of the CYP2E1 derived metabolites
+in plasma following administration of a commercially
+available liquid preparation thus supporting our hypothe-
+sis that a drug vehicle present in the liquid but not solid
+formulation is inhibiting the bioactivating enzymes.
+Previous cell culture and animal experiments and our
+formation rate constant data suggest, but does not prove,
+the PG is the excipient responsible for the effect we
+observed.
+APAP is only sparingly soluble in aqueous solutions
+and consequently solubilizing agents, including PG, are
+necessary in liquid preparations. PG is a known
+competitive inhibitor of CYP2E1.
+21 Given that bioacti-
+vation via the P450 system is necessary for APAP toxicity,
+the effect of PG on APAP toxicity has been studied in
+Table 1. Results of Plasma Analysis (Mean /C6 SEa)
+Solid Liquid P‐Valueb
+Acetaminophen (APAP)
+Peak concentration (µg/mL) 15.4 /C6 1.1 15.7 /C6 1.1 0.811
+Time to peak (minutes) 54.0 /C6 7.9 40.0 /C6 6.3 0.068
+AUCt
+0 (µg h/mL) 51.4 /C6 3.2 54.5 /C6 3.5 0.089
+AUC1
+0 (µg h/mL) 59.6 /C6 4.1 64.1 /C6 4.8 0.143
+APAP‐glucuronide
+Peak concentration (µg/mL) 19.7 /C6 1.0 19.2 /C6 1.3 0.528
+AUCt
+0 (µg h/mL) 107.3 /C6 6.3 109.1 /C6 7.2 0.648
+AUC1
+0 (µg h/mL) 157.2 /C6 10.7 158.1 /C6 9.6 0.922
+APAP‐sulfate
+Peak concentration (µg/mL) 6.20 /C6 0.3 6.50 /C6 0.5 0.266
+AUCt
+0 (µg h/mL) 32.0 /C6 1.5 35.1 /C6 2.6 0.077
+AUC1
+0 (µg h/mL) 45.5 /C6 2.8 51.2 /C6 4.51 0.066
+APAP‐cysteinate
+Peak concentration (µg/mL) 0.42 /C6 0.03 0.34 /C6 0.03 0.003 c
+AUCt
+0 (µg h/mL) 2.41 /C6 0.21 2.01 /C6 0.17 0.007 c
+AUC1
+0 (µg h/mL) 5.70 /C6 0.77 4.29 /C6 0.48 0.007 c
+APAP‐mercapturate
+Peak concentration (µg/mL) 0.136 /C6 0.01 0.116 /C6 0.01 0.016 c
+AUCt
+0 (µg h/mL) 0.716 /C6 0.07 0.602 /C6 0.06 0.006 c
+AUC1
+0 (µg h/mL) 1.51 /C6 0.18 1.09 /C6 0.11 0.005 c
+AUCt
+0 (zero to last observation) are trapezoidal measures and AUC 1
+0
+(zero to infinity) are calculated by nonlinear regression.
+aSE, standard error.
+bPaired sample t‐test, two ‐tailed.
+cStatistically significant at P ¼ 0.05.
+416 The Journal of Clinical Pharmacology / Vol 53 No 4 (2013)
+primary hepatocyte culture as well as in rodents. 14,15,21
+Cultured hepatocytes were less susceptible to APAP ‐
+induced necrosis in the presence of PG. 21 Mice pretreated
+with PG but not fluvoxamine, a CYP1A2 inhibitor,
+showed reduced hepatocellular damage following a toxic
+APAP dose.
+15 In a mouse model, the concept that drug
+vehicles are protective of APAP ‐hepatoxicity has been
+studied: dimethylsulfoxide, dimethylformamide, PG, and
+ethanol were shown to be protective of APAP ‐induced
+liver injury.
+14 Additionally, compared to wild ‐type mice,
+CYP2E1 knock ‐out mice demonstrate minimal increases
+in liver transaminases after an LD 50 dose of acetamino-
+phen; however, at this higher dose, CYP1A2 and CYP3A
+may contribute to NAPQI formation. 22
+Drug–drug interactions affecting APAP toxicity and
+potential manipulation of the P450 system in order to alter
+APAP toxicity in humans is not a new concept. Subjects
+who received 2 months of cimetidine, an established P450
+inhibitor, were noted to have decreased urinary APAP ‐
+mercapturate following therapeutic APAP dosing.
+23
+Cimetidine was proposed as an antidote for APAP
+poisoning, however it was supplanted by the more
+effective N‐acetylcysteine.24 To our knowledge, our study
+is the first to demonstrate the possibility of a drug vehicle
+being protective of APAP ‐hepatoxicity in humans via
+manipulation of the P450 system.
+The formation rate constants were equivalent for the
+phase‐I metabolites between the solid and liquid arms
+(Figure 3). Since, for competitive antagonists such as PG,
+the same enzyme kinetics hold, just at different
+concentration ranges, equivalence of formation rate
+constants supports our hypothesis that PG was functioning
+as a CYP2E1 competitive inhibitor in the liquid group.
+This is also consistent with the dose ‐dependent protective
+effect of PG seen in mice.
+14
+Limitations of our study include that we were unable to
+measure small concentrations of PG; we were unable to
+measure the decline in minor metabolites as they
+Figure 2. Concentration‐time curves for acetaminophen and metabolites. A: Acetaminophen (B) Phase II metabolites (C) CYP2E1 metabolites (Solid
+line represents solid preparation, dashed line represents liquid preparation. Error bars represent /C6 standard error)
+Ganetsky et al. 417
+approached zero; and there was a difference in bioavail-
+ability between liquid and solid formulations. Since the
+PG concentration was 5% (v/v) in the preparation we
+administered, the peak predicted PG concentration would
+be 4.0 mg/dL, assuming an ideal instantaneous absorp-
+tion, a speci fic gravity of PG of 1.04 g/mL; and a volume
+of distribution of 0.58 L/kg. This is very close to the mean
+PG concentration that we observed and helps explain why
+we were unable to detect propylene glycol in six of the 15
+samples, as the limit of detection of the assay available to
+us was 5.0 mg/dL.
+We could only observe our subjects for 9 hours and
+thus we were unable to follow the minor metabolite
+concentrations as they approached zero. We therefore had
+to apply a nonlinear regression model to extrapolate the
+concentrations out to in finity. Regardless, the measured
+plasma AUC ’s are consistent with the modeled AUC ’s;
+the measured results showed a 16 –17% decrease in minor
+metabolite production in the liquid group and when
+extrapolated, this decrease is actually 25 –28%.
+Even though we administered equivalent liquid and
+solid doses (as close to 15 mg/kg as possible), there was a
+trend toward greater bioavailability with the liquid
+formulation. As this absorption difference was not
+statistically signi ficant, we did not correct our results
+and performed all analyses based on equal relative
+bioavailability. However, since absorption was greater
+in the liquid group, we would expect an increase in total
+metabolite formation, including P450 derived metabolites;
+the opposite was the case further strengthening our
+conclusions.
+There are several important implications of our
+findings. First, we offer an alternative theory regarding
+the cause of decreased APAP toxicity seen in children. We
+propose that children tolerate APAP ingestion better than
+adults because they tend to ingest the liquid preparation,
+and are thus co ‐ingesting an inhibitor of the toxic
+bioactivation pathway. Previous theories have less well ‐
+grounded support. For example, infants and toddlers have
+a greater capacity for sulfonation, which is thought to be
+protective; however, glucuronidation capacity is de-
+creased resulting in similar overall capacity for phase ‐II
+metabolism as older children and adults.
+8,11 The larger
+ratio of childrens ’ liver to total body size has been
+proposed to allow them to tolerate a greater milligram per
+kilogram APAP dose than adults, however no data have
+been presented to support this.
+10 Our data suggests it is the
+preparation of drug, rather than the age of patient, which is
+responsible for the observed phenomenon of decreased
+susceptibility to acetaminophen poisoning in children.
+More importantly, we propose that a less hepatotoxic
+formulation of APAP can be developed if co ‐formulated
+with a safe CYP2E1 inhibitor. Co‐formulation with APAP
+to prevent toxicity is not a novel idea; a formulation with
+Figure 3. Formation rate constants for APAP derived metabolites following administration of liquid versus solid preparations.
+418 The Journal of Clinical Pharmacology / Vol 53 No 4 (2013)
+methionine has previously existed and a formulation with
+N‐acetylcysteine has been proposed. 25 However, methio-
+nine itself has toxicity and N‐acetylcysteine has a foul
+odor. Even though PG is a common excipient and
+generally considered safe, it might not be the ideal
+inhibitor to formulate with APAP. Our data suggest that
+higher PG dosing will be needed to achieve greater than
+25% CYP2E1 inhibition; PG has well ‐defined toxicity
+when given intravenously
+26 and likely has toxicity at
+higher oral dosing as well. 27
+Finally, our study highlights the fact that pharmaceuti-
+cal excipients can affect toxicity, pharmacokinetics or
+other aspects of drug effects. While this is unlikely to
+surprise members of the regulatory community or those
+working in the pharmaceutical industry, it is our
+impression that this is less frequently considered by
+clinicians and clinical investigators.
+28
+Conclusions
+Ingestion of liquid relative to solid preparations of APAP
+in therapeutic doses results in a 16 –28% decrease in the
+toxic CYP2E1 metabolites. This is likely due to the
+inhibition of CYP2E1 by PG, and may explain the
+decreased susceptibility of children to APAP toxicity. A
+less hepatotoxic formulation of APAP can potentially be
+developed if co ‐formulated with a CYP2E1 inhibitor.
+Acknowledgments
+We would like to thank Samantha Koehler for her efforts in
+recruiting and coordinating subject visits, as well as Jim Wareing
+and the nursing staff at the Clinical Research Center. We would
+like to thank Elinita Rosseto for her work with regulatory
+documents and the IRB process. We would like to thank
+Dr. Simon C. Robson for guidance and generous use of space.
+We would also like to thank Isaac Bernstein ‐Hanley for his
+support at the Harvard Catalyst in the Harvard Clinical and
+Translational Science Center.
+Declaration of Conflicting Interests
+None.
+Funding
+This work was conducted with support from Harvard Catalyst,
+The Harvard Clinical, and Translational Science Center (NIH
+Award #UL1 RR 025758 and financial contributions from
+Harvard University, its af filiated academic health care centers
+and from the National Center for Research Resources). This
+content is solely the responsibility of the authors and does not
+necessarily represent the of ficial views of Harvard Catalyst,
+Harvard University, and its af filiated academic health care
+centers, the National Center for Research Resources, or the
+National Institutes of Health.
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papers/PKDB00124.md

@@ -0,0 +1,16 @@
+# Paracetamol disposition in normal subjects and in patients treated with antiepileptic drugs.
+
+E Perucca, A Richens
+
+*British journal of clinical pharmacology* (1979)
+
+PMID: 760753
+DOI: 10.1111/j.1365-2125.1979.tb00922.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+1 The serum concentration profile of paracetamol has been determined after administration of single 1000 mg intravenous and oral doses in six normal subjects and six epileptic patients on chronic antiepileptic drug therapy. The urinary excretion of free and conjugated paracetamol has also been determined. 2 Following intravenous administration, serum paracetamol concentration declined with first-order kinetics. Both elimination rate and total body clearance were higher in the epileptic patients, although in neither case was the difference statistically significant. 3 The oral bioavailability (mean +/- s.e. mean) was significantly lower in the epileptic patients than in the normal subjects (0.77 +/- 0.03 and 0.89 +/- 0.02 respectively, P less than 0.01), whereas the urinary excretion total (free+conjugated) paracetamol was almost identical in the two groups. 4 It is suggested that the lower bioavailability of paracetamol in the epileptic patients results from enhancement of first-pass metabolism, secondary to enzyme induction.

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+Br.J.clin.Phannac.(1979),7,201-206
+PARACETAMOLDISPOSITIONINNORMAL
+SUBJECTSANDINPATIENTSTREATED
+WITHANTIEPILEPTICDRUGS
+E.PERUCCA
+ChalfontCentreforEpilepsy.ChalfontSt.Peter,Buckinghamshire
+A.RICHENS
+DepartmentofClinicalPharmacology,St.Bartholomew'sHospital,
+LondonEC1A7BEand
+TheInstituteofNeurology,TheNationalHospital,Queen'sSquare,
+LondonWC1N3BG
+I Theserumconcentrationprofileofparacetamolhasbeendeterminedafteradministrationofsingle
+1000mgintravenousandoraldosesinsixnormalsubjectsandsixepilepticpatientsonchronic
+antiepilepticdrugtherapy.Theurinaryexcretionoffreeandconjugatedparacetamolhasalsobeen
+determined.
+2 Followingintravenousadministration,serumparacetamolconcentrationdeclinedwithfirst-order
+kinetics.Botheliminationrateandtotalbodyclearancewerehigherintheepilepticpatients,although
+inneithercasewasthedifferencestatisticallysignificant.
+3 Theoralbioavailability(mean+s.e.mean)wassignificantlylowerintheepilepticpatientsthanin
+thenormalsubjects(0.77+0.03and0.89+0.02respectively,P<0.01),whereastheurinaryexcretion
+total(free+conjugated)paracetamolwasalmostidenticalinthetwogroups.
+4 Itissuggestedthatthelowerbioavailabilityofparacetamolintheepilepticpatientsresultsfrom
+enhancementoffirst-passmetabolism,secondarytoenzymeinduction.
+Introduction
+Chronicadministrationoftherapeuticagentssuchas
+barbituratesand phenytoin,or exposure to
+environmentalcontaminantssuchasDDT,lindane,
+certainfoodadditives,may inducetheactivityofdrug
+metabolizingenzymes in hepaticmicrosomes
+(Conney,1967;Kuntzman,1969;Parke,1975).A
+largenumberofclinicallyimportantdruginteractions
+havebeenattributedtothismechanism(Breckenridge,
+1975;Hunter& Chasseaud,1976).Inmostcases,the
+interactionsdescribedinvolvedrugswithlowhepatic
+extractionratiosatphysiologicalratesofliverblood
+flow.Forthisgroup ofdrugs(e.g.antipyrine,
+phenylbutazone,coumarinanticoagulants)anincrease
+intherateofhepaticmetabolismresultsina
+shorteningoftheserumhalf-lifeanda reductionin
+steadystateserumconcentration(Wilkinson&Shand,
+1975).
+Thesituationisquitedifferentfordrugswhichhave
+a highhepaticextractionratio.Whereasenzyme
+inductionhasanegligibleeffectontheserumhalf-life
+ofthesecompounds,itmarkedlyreducestheir
+systemicavailabilityafteroraladministration
+(Gibaldi,Boyes& Feldman,1971;Rowland,1972;
+Perrier& Gibaldi,1974;Wilkinson& Shand,1975).
+Althoughthetheoreticalaspectsofthisphenomenon
+havebeencarefullyanalysed,verylittleexperimental
+evidenceisavailableinman (Meikle,Jubiz,
+Matsukura,West&Tyler,1969;Alvan,Piafsky,Lind
+&vonBahr,1977).Inthisstudytheeffectsofenzymeinductiononthe
+dispositionofa drugsubjecttoa relativelyhigh
+hepaticbloodclearancehavebeeninvestigated.The
+kineticsofparacetamolafteroralandintravenous
+dosinghavebeencomparedinhealthysubjectsand
+epilepticpatientstreatedwithknownenzyme-inducingagents.Paracetamolhasbeenselectedasamodeldrug
+becauseitisalmostcompletelyeliminatedby
+biotransformation,mainlyintheliver(Mrochek,
+Katz,Christie& Dinsmore,1974;Koch-Weser,
+1976),andhasamoderatelyhighextractionratioas
+indicatedbyabloodclearanceofapproximately350
+ml/minandevidenceoffirst-passeffectattherapeuticdosages(Rawlins,Henderson& Hijab,1977).Furthermore,paracetamolhasbeenpreviouslyused
+asamodeldruginpharmacokineticstudiesdesigned
+toassesschangesintherateofdrugmetabolism
+202 E.PERUCCA&A.RICHENS
+(Shively& Vesell,1975;Triggs,Nation,Long&
+Ashley,1975).
+Methods
+Subjects
+Sixhealthyvolunteersandsixepilepticpatients,whose
+agesrangedfrom19to42years,consentedtotake
+partinthestudy.Thetwogroupswereclosely
+matchedforage,sexandbodyweight.Thehealthy
+subjectshadnotbeenbeenreceivingdrugtherapy
+regularlyforatleast6monthsprecedingthestudy.
+TheepilepticpatientswereresidentsattheChalfont
+CentreforEpilepsy,andwerereceivingchronic
+treatmentwitha combinationofatleasttwo
+antiepilepticdrugsknownto produceenzyme
+induction(phenobarbitone,primidone,phenytoinand
+carbamazepine).Theonlyexceptionwasa42-year-old
+epilepticpatientwhowasreceivingphenytoinalone
+(400mgdaily).
+Eachsubjectreceivedthefollowingtwotreatments
+inrandomorderseparatedbya 1-weekinterval:a
+singleoraldose(1000mg)ofparacetamol,anda
+similardoseinjectedintravenouslyover5min.The
+oralpreparationwasintheformofeffervescent
+paracetamol(Panadoleffervescent,Winthrop)
+dissolvedin75ml water.Forintravenoususe
+paracetamol(50mg/ml)wasdissolvedinasterile
+vehicleof40%v/vpropyleneglycoland10%v/v
+ethylalcoholinwater.Inordertoavoidtheeffectsof
+circadianvariationsinthedispositionofparacetamol
+(Shively& Vesell,1975),thetimeofadministration
+waskeptconstantat08.00hafteranovernightfast.
+Bloodsamples(10ml)weretakenat0.5,1,1.5,2,3,
+4,5and6hafteradministration.A urinesamplewas
+collectedovertheperiodofbloodsampling.Apart
+fromslightirritationattheinjectionsiteduring
+intravenousinjection,no adverseeffectswere
+observed.
+Measurementofparacetamolconcentrationinserum
+andurine
+Theconcentrationoffree(unconjugated)paracetamol
+wasdeterminedinserum(2ml)andurine(1ml)samplesbygas-liquidchromatographyaccordingto
+themethodofPrescott(1971a).Forthedetermination
+oftotal(freeandconjugated)paracetamol,diluted
+urinesamples(1ml)wereincubatedwithfi-glucuronidasecontainingsulphataseactivity
+(extractedfromHelixpomatia,Sigma)at370Candat
+pH 5.2for20h.Theseconditionswerefoundin
+preliminaryexperimentstobeoptimalforhydrolysis.
+At thecompletionoftheincubationperiodthe
+sampleswereaddedto2ml0.2Mglycinebuffer(pH9.0)andthenextractedaccordingtothemethodof
+Prescott(1971b).Thegas-chromatograph(Perkin
+ElmerF33)wasequippedwithdualflameionization
+detectorsandfittedwithaglasscolumn1.7m long,3
+mm i.d.,filledwith2.5%OV 17onGasChromQ
+100-120mesh.Temperatureswere2350Cforthe
+columnand2750Cforinjectionportanddetector.
+Carriergas(N2)flowwasadjustedtoaninletpressure
+of175kN/m2.
+Pharmacokineticanalysis
+Althoughabicompartmentalmodelhaspreviously
+beenusedtodescribeparacetamolkinetics(Rawlinset
+al.,1977),theshortdistributivephasecouldnotbe
+characterizedaccuratelyinthepresentstudydueto
+thelimitednumberofearlysamples.Akineticanalysis
+could,however,besatisfactorilyperformedaccording
+toaone-compartmentopenmodel.Theelimination
+rateconstant(Kel)wascalculatedbylinearregression
+fromtheterminalpartofthecurve.Theareaunderthe
+curve(AUC)wasdeterminedbythetrapezoidalrule
+andextrapolatedtoinfinity.Thetotalserumclearance,
+Cl,wascalculatedasDose/AUCv (Wilkinson&
+Shand,1975).Thevolumesofdistribution,VdextrapandVdareawerecalculatedrespectivelyasDose/C0
+(whereC0istheconcentrationatzerotime)andas
+Cl/K,g(Odar-CederlofandBorga,1974).
+Theoralbioavailability(F)wascalculatedas
+AUCO_OO/AUC'v0O,.By assumingcomplete
+absorption,F wasalsopredictedforeachindividual
+fromintravenousdataaccordingtotheformula
+(Rowland,1972):
+F=lfm(Dose)
+LBF.L.AUCiv
+wherefmisthefractionmetabolizedbytheliver,A
+theratiooftheconcentrationofparacetamolinwhole
+bloodtotheconcentrationofthedrugintheserum
+andLBFtheliverbloodflow,whichwasassumedto
+be1.55I/min(Levine,1973).Awasdeterminedat
+variousconcentrationsofparacetamolinthree
+epilepticpatientsandintwonormalsubjectsandwas
+foundtoaverage1.18+0.02(s.e.mean)(n=10).fm
+wassubstitutedfor1- fe(wherefeisthefraction
+excretedunchangedintheurine)ontheassumptionthatallmetabolismwashepatic.
+Results
+Afterapproximately1-1.5hfollowingintravenous
+administration,serumparacetamollevelsdeclined
+monoexponentiallyinbothhealthyvolunteersand
+epilepticpatients(Figure1).Followingoral
+administrationinthehealthyvolunteers,serumlevels
+roserapidlywithin0.5htovaluessimilartothose
+foundatcorrespondingtimesafterintravenous
+administration,decliningwitha similarpattern
+PARACETAMOLDISPOSITION203
+E \ \
+CY)
+=0.
+C')
+ 2
+1 2 3 4 5 6
+Time(h)
+Figure1 Serum paracetamolconcentration
+(mean+s.e.mean)afterasingle1000mgi.v.dosein
+sixnormalsubjects(A)andsixepilepticpatients(A)
+thereafter.Thereforethetimeconcentrationcurves
+followingbothroutesofadministrationwerevery
+similar,althoughlevelsweregenerallyslightlylower
+aftertheoraldosing(Figure2).A differentpattern
+wasobservedafteroraladministrationintheepileptic
+patients.Serumlevelsroserapidlywithin0.5hto
+relativelylowpeakvaluesandremainedatall
+samplingtimesclearlylowerthanthoseobservedafter
+intravenousadministration(Figure2).Kinetic
+parameterscalculatedaccordingto a one
+compartmentopenmodelareillustratedinTables1
+and2.ValuesforVdextrapweresimilartothosefor
+Vdarea.Serumhalf-liveswereshorterandtotal
+serumclearanceswerehigherinthepatientsthanin
+thenormalsubjects,butduetotherelativelylarge
+inter-individualvariability,inneithercasewasthe
+differencestatisticallysignificant(0.05<P<0.10).
+Theoralbioavailabilitywasincompleteinboth
+groupsandwassignificantlylowerinthepatientsthan
+inthenormalvolunteers(P<0.01).Therewasa
+relativelygoodagreementbetweenthepredictedand
+theobservedbioavailability,althoughinbothgroups
+predictedvalueswereslightlylowerthanthose
+observed(Table2).Therewasaparticularlygood
+agreementbetweenthepredictedandobserved
+decreaseinoralavailabilityinthepatients(12%and
+13%respectively).
+Therecoveryoftotalandfreeparacetamolinurine
+isillustratedinTable3.About60-70%ofthedose
+couldberecoveredover6hfollowingadministration
+ofthedrug.Therewasno significantdifference
+betweenrecoveriesfollowingoralandintravenous
+administration.Therecoverywasalmostidenticalon
+bothoccasionsinthepatients,whileamarginally
+lowervaluewasobservedinthenormalsubjectsafter
+oraldosing.Thelatterdiscrepancywasentirelydueto
+verylowrecoveryinasinglesubjectinwhomaurine
+voidwaslostduringthecollectionperiod.
+Onlyaverysmallfractionofthedosewasexcreted
+asfreeparacetamol.Theratiooffreetototaldrugin
+theurinewaslowerinthepatientsbutthedifference
+didnotreachstatisticalsignificance.
+Discussion
+The distributionand eliminationkineticsof
+paracetamolafteroralandintravenousadministration
+innormalsubjectshasbeenrecentlyinvestigatedin
+b
+L
+I
+1 2 3 4 5 6
+I I
+1 2 3 4 5 6
+Time(h)
+Figure2 Serumparacetamolconcentration(mean+ s.e.mean)followinga single
+intravenous(A,A)doseina)sixnormalsubjectsandb)sixepilepticpatients.
+1000mg oral(-,0)or
+a
+Jit
+10F0)
+ECu
+0.
+E
+0)c')
+5
+204 E.PERUCCA&A.RICHENS
+Table1 Kineticparameters(mean±s.e.mean)calculatedafterintravenousadministrationofparacetamol
+(1000mg).
+CO(gg/ml)
+Vdextrap(I/kg)
+Vdarea(I/kg)Kel(h-')
+Tj(h)
+AUC0_OO(mg1-'h-1)
+Cl(Ih-1)
+Healthysubjects
+16.0±1.4
+0.94+0.08
+0.96+0.11
+0.292+0.036
+2.52±0.25
+55.3+1.9
+19.3+2.5
+Epilepticpatients
+14.9±2.1
+1.05+0.11
+1.11+0.14
+0.381±0.028
+1.88±0.17*
+38.3±6.4**
+29.4±4.4*
+*P<0.10,**P<0.05(Student'st-test)
+Table2 Kineticparameters(mean+s.e.mean)calculatedafteroraladministrationofparacetamol(1000
+mg).
+Healthysubjects Epilepticpatients
+AUCoral(mg1-1h-1) 49.4+1.8 29.3+5.1**
+F(observed) 0.89+0.02 0.77±0.03*
+F(predictedfromi.v.data) 0.83±0.02 0.73±0.04*
+*P<0.01,* P<0.05(Student'st-test)
+Table3 Recoveryoffreeandconjugatedparacetamolinurineexpressedasmean±s.e.mean
+Healthysubjects
+Totalamountrecovered(free+conjugated(mg)Fractionfree(%)
+Epilepticpatients
+Totalamountrecovered(free+
+conjugated)(mg)Fractionfree(%)
+I.V.
+administration
+657±86
+2.4+0.6
+682±53
+2.0±0.5
+Oral
+administration
+601+72
+2.0+0.4
+677+33
+1.8+0.3
+PARACETAMOLDISPOSITION205
+detailbyRawlinsetal.(1977).Ourdatainnormal
+subjectsareinverycloseagreementwiththeirs.In
+particular,thereisaremarkablesimilarityoftheoral
+bioavailabilitydeterminedaftera1000mgdose(0.89
+in bothstudies)despitetheuseofdifferent
+formulations.Theincompleteoralbioavailabilityof
+paracetamolhasbeeninterpretedasevidenceoffirst-
+passmetabolismon theassumptionthatgas-
+trointestinalabsorptioniscomplete(Rawlinsetal;
+1977).Occurrenceoffirst-passmetabolismisfurther
+suggestedby ourobservationthattheurinary
+recoveryoffreeplusconjugatedparacetamolafter
+oraladministrationwas similarto thatafter
+intravenousadministrationinbothnormalsubjects
+andepilepticpatients.
+Oralbioavailabilitywassignificantlylowerinour
+patientsthaninnormalsubjects.Thisobservationisin
+linewithourhypothesisthatparacetamolmetabolism
+isenhancedby concurrentadministrationof
+antiepilepticdrugs.In fact,by assumingthat
+eliminationisentirelyduetohepaticmetabolism,it
+canbecalculated(Wilkinson& Shand,1975)thatfor
+aliverbloodflowof1.55I/minthehepaticextraction
+ratioaveraged0.17inthenormalsubjectsand0.27in
+thepatients.Accordingtothesevalues,the
+pharmacokineticpatternofparacetamolshouldbe
+intermediatebetweenthatofahighlyextractedand
+thatofa poorlyextractedcompound.Therefore,
+stimulationofitsmetabolismshouldresultina
+moderatedecreaseofbothsystemicavailabilityand
+biologicalhalf-life(Wilkinson& Shand,1975).The
+hypothesisthatfirst-passmetabolismratherthan
+incompleteabsorptionisresponsibleforthelower
+bioavailabilityofparacetamolinepilepticpatientsis
+supportedbytheurinarydataandbythegood
+agreementbetweenpredictedandobserveddecrease
+ofbioavailability.Itisofinterestthatpredictedvalues
+wereslightlylowerthanthoseobserved.The
+discrepancymay beduetotheoccurrenceof
+saturationkineticsduringtheabsorptionprocessor,
+alternatively,topartofmetabolismtakingplace
+outsidetheliver,inwhichcasetheestimatesofhepatic
+extractionratiosgivenabovewoulderronthehigh
+side.
+Thefirsthypothesisissupportedbytheobservation
+thattheoralbioavailabilityofparacetamolis
+significantlyhigheraftera1000mgthanaftera500
+mgdose(Rawlinsetal.,1977).Occurrenceofextra-
+hepaticmetabolismcannotbeexcludedonthebasisof
+ourresultsalonebutthereisconsiderableevidence
+thatthisisunlikely.Paracetamolismetabolized
+mainlybyconjugationwithglucuronicacidand,toa
+lesserextent,withsulphuricacid(Cummings,King&
+Martin,1967).Bothofthesereactionsareknownto
+takeplacelargelyintheliver(Koch-Weser,1976).
+Moreover,thefactthatparacetamolmetabolismisnot
+alteredinanephricpatientscomparedwithnormal
+subjectsindicatesthatthekidneydoesnotplaya
+significantpartinthebiotransformationofthedrug
+(Lowenthal,0ie,vanStone,Briggs&Levy,1976).The
+higherbloodclearanceofparacetamolinepileptic
+patientsislikelytobeaconsequenceofincreased
+hepaticmetabolism(asisalsosuggestedbytheslightly
+lowerratiosoffreetoconjugateddruginthepatients'
+urine),butenzymeinductionperseisnotnecessarily
+themechanisminvolved.
+Althoughtheenzymesystemresponsiblefor
+glucuronideformationisinducible(Blaschke,Berk,
+Rodkey,Scharschmidt,Collison& Waggoner,1974;
+Lecamwasam,1975;Parke,1975),animalstudies
+indicatethatthestimulationofhepaticmicrosomal
+enzymesby phenobarbitoneisassociatedwith
+changesinseveralothermeasuresofliverfunction,
+eachofwhichcouldtheoreticallyresultin
+enhancementofmetabolicdrugclearance.These
+includeincreasedconcentrationinthehepatocyteof
+theY organicanion-bindingprotein(Reyes,Levy,
+Gatmaitan& Arias,1971),increasedbileflow
+(Redinger& Small,1973)andincreasedliverblood
+flow(Ohnaus,Thorgeirsson,Davies& Breckenridge,
+1970;Branch,Shand,Wilkinson& Nies,1974;Nies,
+Wilkinson,Rush,Strother& McDevitt,1977).The
+latterisunlikelytoaccountforthefasterelimination
+ofparacetamolsincethemetabolicclearanceofthis
+druginmanisconsiderablylowerthantheaverage
+bloodflowtotheliver(Lowenthaletal.,1976).
+Apartfromthetheoreticalinterestintermsofa
+pharmacokineticmodel,ourresultsmay have
+importantclinicalimplications.Ithasbeensuggested
+thatthehepatoxicityofparacetamolisrelatedtothe
+formationofatoxichighly-reactivemetaboliteinliver
+microsomes(Mitchell& Potter,1975;Davis,
+Simmons,Harrison& Williams,1976).Inductionof
+itsmetabolismbyotherdrugsmaytheoretically
+increasethesusceptibilitytothedevelopmentofacute
+necrosisoftheliver.Indeed,thishasbeenshowntobe
+thecaseinlaboratoryanimals(McLean&Day,1975)
+andtheobservationthatpatientsreceivingenzyme-
+inducingagentsfareparticularlybadlyaftera
+paracetamoloverdosesuggeststhatasimilareffect
+takesplaceinman(Wright&Prescott,1973).
+We thankDr JohnLaidlaw,SeniorPhysicianatthe
+ChalfontCentreforEpilepsy,forallowingustostudy
+patientsunderhiscare;thenursingstaffoftheChalfont
+Centrefortheirhelp,andtheChalfontResearchFundand
+McAlpineFoundationforfinancialsupport.
+14
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+ROWLAND,M.(1972).Influenceofrouteofadministration
+ondrugavailability.J.Pharm.Sci.,61,70-74.
+SHIVELY,C.A.&VESELL,E.S.(1975).Temporalvariations
+inacetaminophenandphenacetinhalf-lifeinman.Clin.
+Pharmac.Ther.,18,413-424.
+TRIGGS,EJ.,NATION,R.L.,LONG,A.& ASHLEY,JJ.
+(1975).Pharmacokineticsintheelderly.Eur.J.clin.
+Pharmac.,8,55-62.
+WILKINSON,G.R.&SHAND,D.G.(1975).Aphysiologicalapproachtohepaticdrugclearance.Clin.Pharmac.
+Ther.,18,377-390.
+WRIGHT,N.& PRESCOTT,L.F.(1973).Potentiationbypreviousdrugtherapyofhepatotoxicityfollowing
+paracetamoloverdosage.Scot.med.J.,18,56-58.
+(ReceivedMarch21,1978)

papers/PKDB00136.md

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+# Simultaneous LC-MS/MS analysis of the plasma concentrations of a cocktail of 5 cytochrome P450 substrate drugs and their metabolites.
+
+Shimako Tanaka, Shinya Uchida, Naoki Inui, Kazuhiko Takeuchi, Hiroshi Watanabe, Noriyuki Namiki
+
+*Biological & pharmaceutical bulletin* (2014)
+
+PMID: 24389476
+DOI: 10.1248/bpb.b13-00401
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+A "cocktail" approach, which involves simultaneous administration of multiple CYP-specific probes, concurrently detects the activity of multiple CYP enzymes. We developed and validated a rapid and selective LC-MS/MS method for determining the plasma concentrations of 5 CYP probe drugs and metabolites (caffeine/paraxanthine, CYP1A2 substrate; losartan/losartan carboxylic acid (E3174), CYP2C9 substrate; omeprazole/5-hydroxyomeprazole, CYP2C19 substrate; dextromethorphan/dextrorphan, CYP2D6 substrate; and midazolam/1'-hydroxymidazolam, CYP3A4 substrate) by single-step extraction, followed by a single LC-MS/MS run. An Ostro™ 96-well plate was used for extraction of CYP substrates and metabolites from human plasma and urine. Following optimization of the chromatographic conditions, all the peaks were well separated, and retention times ranged between 4.4 and 11.7 min. The total run time for a single injection was within 13 min. The accuracy and precision values suggested that the assay had high accuracy and reliability in plasma and urine samples. No significant matrix interference was observed. To demonstrate the efficacy of this method, plasma and urine concentrations of 5 CYP probe substrates and their metabolites were determined after simultaneous oral administration of 5 drugs to 4 healthy volunteers. All the substrates and metabolites were detected over an 8 h period, and the plasma concentrations of each substrate at 8 h after administration were above the lower limit of quantification. Urine concentrations of drugs and their metabolic ratio were evaluated after the administration. In conclusion, the advantage of our cocktail approach is that it enables in vivo assessment of the activity of various drug-metabolizing enzymes in a single assay.

papers/PKDB00136.pdf

@@ -0,0 +1,3 @@
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papers/PKDB00151.md

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+# Effects of microsomal enzyme induction on paracetamol metabolism in man.
+
+L F Prescott, J A Critchley, M Balali-Mood, B Pentland
+
+*British journal of clinical pharmacology* (1981)
+
+PMID: 7306429
+DOI: 10.1111/j.1365-2125.1981.tb01193.x
+
+---
+
+**Note: This article is not available on PubMed Central (Open Access). Only the abstract is included below.**
+
+## Abstract
+
+1 The metabolism of paracetamol after a single oral dose of 20 mg/kg was compared in fifteen patients with microsomal enzyme induction taking anticonvulsants or rifampicin and twelve healthy volunteers. 2 Induction was confirmed by measurement of the plasma antipyrine half-life (mean 6.4 h in the patients compared with 12.8 h in the volunteers). 3 The glucuronide conjugation of paracetamol was enhanced in the induced patients as shown by lower plasma paracetamol concentrations, a shorter paracetamol half-life, higher paracetamol glucuronide concentrations and an increased ratio of the area under the plasma concentration time curves of the glucuronide to the unchanged drug. There were no significant differences in sulphate conjugation. 4 There was a corresponding change in the pattern of urinary metabolite excretion. The induced patients excreted significantly less unchanged drug and sulphate conjugate and more glucuronide conjugate than the healthy volunteers. 5 The urinary excretion of the mercapturic acid and cysteine conjugated of paracetamol was the same in both groups. 6 Conversion of paracetamol to its potentially hepatotoxic metabolite does not seem to be increased in patients induced with anticonvulsants or rifampicin. There would seem to be no contraindication to the use of these drugs in combination.

papers/PKDB00151.pdf

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