Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing

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1 Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing Susanne Ammon, Ute Hofmann, Ernst-Ulrich Griese, Nadja Gugeler & Gerd Mikus Dr Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, PO Box 5112, D 7341 Stuttgart, Germany Aims The pharmacokinetics of dihydrocodeine (DHC) and its active metabolite dihydromorphine (DHM) were assessed after a single oral dose of DHC and after increasing doses of DHC at steady-state. Methods Twelve healthy male volunteers (18 45 years, CYP2D6 extensive metabolizers (EMs), MR<1 took a single oral dose (s.d.) of DHC 6 mg after breakfast. After 6 h DHC 6 mg was administered twice daily for 3 days, the dose was increased to 9 mg twice daily for 3 days, the final dose of 12 mg was administered twice daily for 3 days (multiple dose: m.d.). Blood sampling and urine collection: during 6 h after s.d. and during 12 h after m.d. Results No significant differences in the area under the curve (AUC) of both, DHC and DHM could be detected after a single oral dose of 6 mg DHC (AUC (,2)) and during steady-state doses of 6 mg DHC (AUC(,12 h)). During increasing steady-state doses of DHC, the data showed a dose linearity of AUC, maximal serum concentration (C max ) and minimal steady-state serum levels (C ss min) of both, DHC and DHM (P<.1), point estimates of DHC dose corrected AUCs were well within the bioequivalence range (6 mg:.989; 9%CI , 9 mg:.997; 9%CI , 12 mg:.977; 9%CI ). O-demethylation from DHC to DHM remained constant within the increasing steady-state doses of DHC in the 12 extensive metabolizers of CYP2D6. Conclusions In the studied dose range (6 12 mg) the pharmacokinetics of DHC and its active metabolite DHM are linear in EMs of CYP2D6. Keywords: dihydrocodeine, dihydromorphine, multiple dose, pharmacokinetics, single dose Introduction Further in vitro studies with human liver microsomes confirm these results; additionally it could be demonstrated Dihydrocodeine (DHC) is a semisynthetic opioid which that the formation of a second primary metabolite is frequently used as an analgesic (WHO step 2) and of DHC, nordihydrocodeine, is predominantly catalysed antitussive drug. Furthermore, doses up to 25 mg day 1 by CYP3 A4 [9]. The third primary metabolite is DHC- are prescribed in substitution therapy for heroin drug 6-glucuronide [3]. In clinical studies of Eckhardt et al. addicted people. Data on the pharmacokinetics and [1] and Poulsen et al. [11] analgesic effects of codeine metabolism as well as pharmacodynamics of DHC are could be demonstrated only in extensive and not in poor very limited [1 4]. DHC is structurally related to the metabolizers of CYP2D6 using the cold pressure test as natural occurring opioid codeine. In several studies it has a pain model, indicating that the O-demethylated been demonstrated that codeine O-demethylation to metabolite morphine is responsible for the analgesic morphine is mediated by the polymorphically expressed effects of codeine in extensive metabolizers of CYP2D6. enzyme CYP2D6 [5 8]. Recently it was shown that Similar analgesic mechanisms can be proposed for DHC, DHC is also a substrate of the polymorphic enzyme although in one recent study analgesic activity was not CYP2D6 and the formation of the metabolite dihydromorphine diminished in quinidine-induced poor metabolizers after (DHM) is catalysed mainly by this enzyme [3]. a single dose of DHC using different pain models [12]. Regarding the impact of high steady-state doses of Correspondence: Dr S. Ammon, Dr Margarete Fischer-Bosch-Institut für DHC in the treatment of chronic pain and in substitution Klinische Pharmakologie, PO Box 5112, D 7341 Stuttgart, Germany. Tel: , Fax: , susanne.ammon@ikp-stuttgart.de. therapy, pharmacokinetic data during higher steady-state Received 22 December 1998, accepted 16 June doses of DHC and its metabolites are lacking. In addition, 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48,

2 S. Ammon et al. there is no knowledge about a possible saturation of the O-demethylating enzyme CYP2D6 during increasing steady state-doses of DHC. Therefore, the aim of our study was to assess the pharmacokinetics of DHC and its probable active metabolite DHM after multiple increasing doses of DHC under steady-state conditions in comparison with a single oral dose of DHC. Because of the genetic polymorphism, only extensive metabolizers of CYP2D6 were included in this study. 12, 12 24, and 48 6 h after administration of single dose (6 mg) and during the last dosing interval (12 h) of each of the three dihydrocodeine dose regimens. A 1 ml aliquot of each urine sample was stored at 2 C until analysed. Vital signs (heart rate, blood pressure, respiration) and adverse events were assessed frequently before each drug administration and until 8 h post administration. Methods Study medication Subjects CodicontinA; active compound: Dihydrocodeine tartrate (MWt: ). Twelve healthy male Caucasian volunteers, extensive Formulation, strength: sustained release tablet with metabolizers of the CYP2D6 polymorphism, median age 6, 9, 12 mg dihydrocodeine tartrate Manufacturer: 3 years (23 4 years), median weight 75 kg (67 86 kg), Mundipharma GmbH, Basel, Switzerland. median BMI 23 kg m 2 (21 27 kg m 2 ), participated in the study. The study had been approved by the ethics commitee Analytical measurements of the local medical board (Landesärztekammer Baden Determination of dihydrocodeine and dihydrocodeine Württemberg) according to the ethical guidelines of the metabolites in serum and urine using a modified 1975 Declaration of Helsinki. All volunteers gave their GC MS MS method of Hofmann et al. [16]. 1 pmol written informed consent prior to inclusion. [ 2 H 3 ]-dihydromorphine and 25 pmol [ 2 H 3 ]-dihydroco- The subjects were healthy according to history, physical deine were added as internal standards to 1 ml serum. examination and laboratory tests, had no history of drug Extraction was performed as described, and the pentaabuse and did not take any medication. The volunteers fluoropropionyl derivatives prepared by treatment with had been previously phenotyped with respect to sparteine 3 ml pentafluoropropionic anhydride, 1 ml pentaoxidation with a single dose of 1 mg sparteine sulphate fluoropropanol and 2 ml acetonitrile for 3 min at 6 C. and subjects were classified according to the urinary The limits of quantification were 1 pmol ml 1 serum metabolic ratio (MR) of sparteine and its 2- and for dihydrocodeine and 5 fmol ml 1 serum for dihydro- 5-dehydrometabolite [13]. In order to minimize the morphine. Quality control samples of dihydrocodeine variability of CYP2D6, only subjects with a MR<1 (1., 1, 5 and 1 pmol ml 1 ) and dihydromorwere included in this study. With regard to genotyping, phine (.1, 2., 5. and 15. pmol ml 1 ) were routinely using the methods of Stüven et al. [14] and Griese et al. assayed with an intra-assay coefficient of variation of [15], there was no genotype specific for poor metabolizers 1.2% or better and an interassay coefficient of variation of CYP 2D6. less than 14%. Dihydromorphine and dihydrocodeine in urine (5 ml) were determined after 152 dilution with Study design water as described above. The total amounts of dihydrocodeine and dihydromorphine (free and conjugated) were The study was performed as an open study with each subject receiving first a single oral dose of dihydrocodeine measured in a 152 dilution of 5 ml urine in water after 6 mg after breakfast with 1 ml water. After 6 h acid hydrolysis (33 ml 37% hydrochloric acid) at 1 C 6 mg dihydrocodeine was administered twice daily for for 45 min. Dihydrocodeine bitartrate was obtained from 3 days, thereafter the dose was increased to 9 mg twice Merck (Darmstadt, Germany), and dihydromorphine daily for 3 days, thereafter the highest dose of 12 mg hydrochloride was a gift from Mundipharma (Limburg, was administered twice daily for 3 days. Germany). After single dose (6 mg) blood samples were taken before and.5, 1, 2, 3, 4, 5, 6, 8,1, 12, 24, 25, 35, 36, 48 and 49 h after administration, after multiple dosing Pharmacokinetic evaluation before and 1, 2, 3, 4, 5, 6, 8, 1, 12 h after the sixth Standard noncompartmental analysis for calculations using (last) administration of each dihydrocodeine dose regimen. serum concentration-time data was performed with Blood samples were centrifuged after 3 min and TOPFIT 2. (Gustav Fischer Verlag 1993). serum was stored at 2 C until analysed. The following pharmacokinetic parameters of dihydro- Urine was collected before drug administration, at codeine (DHC) and dihydromorphine (DHM) were Blackwell Science Ltd Br J Clin Pharmacol, 48,

3 Pharmacokinetics of dihydrocodeine determined from the serum concentration-time data und Additional assessment of bioequivalence under single the urine concentration data: and multiple dose conditions: bioequivalence testing was C max peak serum concentration ( pmol ml 1 ): obtained performed by calculating the individual ratios from visual inspection of the serum concentration-time test/reference (test=dose corrected AUC multiple curves of DHC and DHM dose, normalized to 6 mg DHC dose; reference=auc t max time to attain peak serum concentration (h): 6 mg single dose). obtained from visual inspection of the serum concen- Point estimates (geometric means) and shortest 9% tration time curves of DHC and DHM CI after logarithmic transformation and re-transformation t 1/2 terminal phase half-life calculated according to were given for the ratios. Test was considered bioequivalent ln(2)/l z (h) to reference if the 9% CI of the AUCs(,2) (single AUC area under the serum concentration time curve dose) and AUC(,12 h)(multiple dose) ratios were within (nmol l 1 h): calculated by the trapezoidal rule, the (Statgraphics Plus 2.) segment to infinity was determined from the last In order to verifiy if steady-state was reached, a concentration measured divided by the elimination rate Wilcoxon matched pairs signed rank test was applied to constant (single dose); AUC after multiple doses was the DHC serum concentrations before the last dose of calculated by the trapezoidal rule using the serum each dose level and the concentration measured 12 h concentration time data during the dosing interval thereafter. (,12 h). ratio AUC AUC DHC: AUC DHM Ae cumulative amount of drug or metabolite excreted Results in urine [% of dose] The serum time-concentrations of dihydrocodeine CLo apparent oral clearance of DHC determined by (DHC) and dihydromorphine (DHM) after single and dose p.o. /AUC p.o. (ml min 1 ) multiple oral dosages of DHC are presented in Figures 1, CL met DHCDHM metabolic clearance of DHC to 2a and 2b. DHM calculated as Ae total DHM No significant differences in the area under the curve (free+glucuronidated)/auc DHC (ml min 1 ). The (AUC) of both, DHC and DHM could be detected after true CL met is probably higher due to the formation of a single oral dose of 6 mg DHC and during steady-state nordihydromorphine and its glucuronides. doses of 6 mg DHC. The mean percentage extrapolation CL met DHCDHC-G metabolic clearance of DHC of AUC to infinity after single dose was.3% (95% CI to DHC-glucuronide calculated as Ae DHCglucuronide/AUC.2.4) for DHC and 6.2% (95% CI ) for DHM. DHC (ml min 1 ) Concerning DHC, there were no significant changes in CL met DHMDHM-G metabolic clearance of DHM apparant oral clearance (CLo), glucuronidation (C met to DHM-glucuronide calculated as Ae DHM- DHCDHC-G) and renal clearance (CL ren ). In addition, glucuronide/auc DHM (ml min 1 ) no significant difference in the urinary excretion of total CL ren DHC renal clearance of DHC calculated as Ae free DHC/AUC DHC (ml min 1 ) CL ren DHM renal clearance of DHM calculated as Ae free DHM/AUC DHM (ml min 1 ) 4 1 C ss min minimal steady-state-concentration of DHC: 8 average of values of h and 12 h of the dosing interval 3 (pmolml 1 ) during multiple dose. 6 2 Statistical evaluation 4 The data are presented as mean±95% CI. Statistical analysis of the obtained pharmacokinetic 1 2 parameters within the different DHC doses were performed with a repeated measures anova analysis using the statistical program Instat 3. (Graphpad Software, ). If anova supported a statistically significant difference ( P<.5), Bonferroni multiple comparison Time (h) test was performed as post test. All statistical tests were Figure 1 Serum time concentrations of DHC (#) and DHM performed as two-tailed test with a level of significance (6) after 6 mg DHC single dose; blood sampling: 49 h; n= of.5. 12; mean±s.d. Dihydrocodeine (pmol ml -1 ) Dihydromorphine (pmol ml -1 ) 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48,

4 S. Ammon et al. Dihydrocodeine (pmol ml -1 ) Dihydromorphine (pmol ml -1 ) a b dose), free DHC represented 23.5% of dose, total DHM represented 5.4% of dose in urinary recovery. The pharmacokinetic data show an increase of AUC, maximal serum concentration (C max ) and minimal steadystate serum levels (C ss min) of both, DHC and DHM after increasing steady-state doses of DHC ( P<.1) (Tables 1 and 2). In contrast, no significant dosedependent differences were observed concerning apparant oral clearance of DHC, renal clearance of DHC and partial metabolic clearance from DHC to DHC-glucuronide and to the O-demethylated metabolite DHM (Tables 1 and 2). DHC O-demethylation to DHM remained constant within the increasing steady-state doses of DHC in the 12 extensive metabolizers of CYP2D6: Regression analysis of the ratios AUC DHC/AUC DHM demonstrated no significant changes within the three steadystate doses (Figure 3). In addition, there was no significant difference in the urinary excretion of DHC and DHM (Table 2). Additional assessment of bioequivalence of DHC after single and multiple doses of DHC Dose corrected AUCs (AUC per mg dose, normalized to 6 mg dose) of DHC and DHM after the three multiple doses (DHC 6 mg, 9 mg, 12 mg) were tested Time (h) in reference to corresponding AUC obtained after 6 mg DHC single dose administration. Point estimates and Figure 2 a) Serum time concentrations of DHC after 6 mg shortest 9% CI were all inbetween the bioequivalence (#), 9 mg (6), 12 mg (1)DHC multiple dose; blood ranges from.8 to ( ),.997 sampling: 12 h; n=12; mean±s.d. and b) Serum time ( ),.977 ( ) for DHC,.949 concentrations of DHM after 6 mg (6), 9 mg (%), 12 mg ( ),.972 ( ),.974 ( ) (#) DHC multiple dose; blood sampling: 12 h; n=12; mean±s.d. for DHM. DHC+total DHM (free+glucuronidated drug) was observed (see Table 1, 2). After single dose administration glucuronidated DHC was the main metabolite (49.3% of Steady-state For each of the three different doses (6, 9, 12 mg) steady-state was achieved as no differences in DHC Table 1 Pharmacokinetic data of DHC after single dose (s.d.) and multiple doses (m.d.) (n=12; mean, 95% CI). AUC C max C ssmin CLo DHC DHC CL ren Dose DHC DHC DHC DHC DHC-G DHM DHC DHC (nmol l 1 h) ( pmol ml 1 ) ( pmol ml 1 ) (ml min 1 ) (ml min 1 ) (ml min 1 ) (ml min 1 ) CL met CL met 6 mg s.d ( ) (312 37) (67 79) ( ) (29 43) ( ) 6 mg m.d ( ) (43 543) ( ) ( ) ( ) (35 56) ( ) 9 mg m.d ( ) ( ) ( ) (594 74) ( ) (32 54) ( ) 12 mg m.d ( ) ( ) ( ) (63 86) ( ) (37 54) ( ) Blackwell Science Ltd Br J Clin Pharmacol, 48,

5 Pharmacokinetics of dihydrocodeine Table 2 Pharmacokinetic data of DHM and urinary excretion of total DHC and DHM (free+glucuronidated drug) after single dose (s.d.) and multiple doses (m.d.) (n=12; mean, 95% CI). CL met AUC C max C ssmin DHM CL ren Ae Dose DHM DHM DHM DHM-G DHM total DHC+total DHM DHC (nmol l 1 h) ( pmol ml 1 ) (pmol ml 1 ) (ml min 1 ) (ml min 1 ) (% of dose) 6 mg s.d (51 89) ( ) ( ) (15 215) (74 82) 6 mg m.d (44 85) ( ) ( ) ( ) ( ) (82 98) 9 mg m.d (75 123) (9.8 16) (5.1 9.) ( ) (27 294) (73 1) 12 mg m.d (98 167) (13 23) (8.1 13) ( ) ( ) (78 18) Ratio AUC DHC/AUC DHM Dose DHC (mg) and its active metabolite DHM are linear in extensive metabolizers of CYP2D6; there was a linear, dose dependent increase of AUC, C max and C ss min of both, DHC and DHM, for the three doses of DHC used. Clearance of DHC and DHM (CLo, partial metabolic clearance from DHC to DHC-glucuronides, DHC to DHM, DHM to DHM-glucuronides, CL ren of DHC and DHM and renal excretion were not affected during the three steady-state doses of DHC, indicating that metabolism and excretion of DHC and its metabolites are not dose-dependent. There is further evidence from in vitro data with human liver microsomes that formation of DHC-metabolites is linear because of high K m values for O-demethylation (981 mm), N-demethylation (9541 mm) and glucuronid- ation (1566 mm) of DHC [9, 17]; these K m values are more than 1-fold higher than the maximal serum concentrations of DHC after 12 mg multiple dosing in this study. Bioequivalence assessment of dose corrected AUCs Figure 3 Regression analysis: Ratio AUC DHC/AUC DHM and the corresponding DHC doses (mg) after multiple doses of DHC; n=12; slope:.9±.12; 95%CI of slope;.33,15; P: NS. serum concentrations were observed between C ss min before the last dose of each dose interval and 12 h after the last dose. after single and multiple doses demonstrated point estimators and 9% CI well within the range of , Side-effects therefore the dose corrected AUCs in the dose range studied can be regarded as bioequivalent with the single Opiate related side-effects occurred especially during dose AUC. higher steady state doses of DHC: headache, nausea, The AUC ratios DHC/DHM did not differ between vomiting, dizziness, constipation, pain of stomach, mild the three steady-state doses, indicating that there is no urinary retention, dry mouth, and mild euphoria. The saturation of CYP2D6-depending O-demethylation of side-effects were mild and reversible and none of the subject had to discontinue the study. DHC in extensive metabolizers. These data are in agreement with Mikus et al. [18], who could show that Discussion the AUC ratios DHC/DHM in EM subjects undergoing DHC replacement therapy for opioid dependence using Although DHC is included in the treatment of chronic daily doses of mg DHC (actual given single pain (WHO step 2), there is a lack of pharmacokinetic dose before blood sampling mg) were in the data especially during increasing steady-state doses of same range. DHC. Our data show that in the dose range studied The pharmacokinetic parameters for DHC after single (6 12 mg twice daily) the pharmacokinetics of DHC dose are similar to those reported by Fromm et al. [3] 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48,

6 S. Ammon et al. using the same amount of DHC, confirming the results 4-hydroxylation. Biochem Biophys Res Commun 1988; 152: of that study Dihydrocodeine is structurally related to codeine. 7 Yue QJ, Svennson JO, Alm C, Sjöquist F, Säwe J. Codeine O-demethylation co-seggregates with polymorphic Codeine O-demethylation is also mediated by the debrisoquine hydroxylation. Br J Clin Pharmacol 1989; 28: polymorphic enzyme CYP2D6 [5 7]. The pharmaco kinetics of codeine appears to be linear [19]. The major 8 Mikus G, Trausch B, Rodewald C, et al. Effects of codeine metabolic pathway of codeine is the formation of on gastrointestinal motility in relation to CYP2D6 codeine-6-glucuronide. O-demethylation of codeine to phenotype. Clin Pharmacol Ther 1997; 61: morphine constitutes a minor pathway accounting for 9 Kirkwood LC, Nation RL, Somogyi AA. Characterisation of about 7% of the dose administered [19, 2]. In our study, the human cytochrome P45 enzymes involved in the metabolism of dihydrocodeine. Br J Clin Pharmacol 1997; 44: the Ae of total DHM was 6.7%, 6.5% and 6.7% for the three steady-state doses of DHC. 1 Eckhardt K, Li S, Ammon S, Schänzle G, Mikus G, Comparing the pharmacokinetics of DHC after 6 mg Eichelbaum M. Same incidence of adverse drug events after single dose and 6 mg multiple dose, our data show no codeine administration irrespective of the genetically differences in the AUC of DHC,CLo, clearance to determined differences in morphine formation. Pain 1998; DHC-glucuronides, renal clearance of DHC and the 76: urinary recovery of total DHC and DHM; partial 11 Poulsen L, Brosen K, Arendt-Nielsen L, Gram LF, Elbaek K, Sindrup SH. Codeine and morphine in extensive and metabolic clearance from DHC to DHM increased poor metabolizers of sparteine: pharmacokinetics, analgesic slightly, just reaching statistical significance, but it did not effect and side effects. Eur J Clin Pharmacol 1996; 51: differ between the three steady-state doses In conclusion, in the dose range studied (6 12 mg) 12 Wilder-Smith CH, Hufschmid E, Thormann W. The the pharmacokinetics of DHC and its active metabolite visceral and somatic antinociceptive effects of DHM were linear in extensive metabolizers of CYP2D6. dihydrocodeine and ist metabolite, dihydromorphine. A There was a linear, dose dependent increase of AUC, cross-over study with extensive and quinidine-induced poor metabolizers. Br J Clin Pharmacol 1998; 45: C max and C ss min of both, DHC and DHM, within the 13 Eichelbaum M, Bertilsson L, Säwe J, Zekorn C. three steady-state doses of DHC. Metabolic ratio, Polymorphic oxidation of sparteine and debrisoquine: related clearance and renal excretion were not affected, indicating pharmacogenetic entities. Clin Pharmacol Ther 1982; 31: that metabolism and excretion of DHC and its metabolites is not dose dependent. The study was supported by the Robert Bosch Foundation, 14 Stüven T, Griese E-U, Kroemer HK, Eichelbaum M, Zanger U. Rapid detection of CYP2D6 null alleles by long distance and multiplex polymerase chain reaction. Stuttgart, Germany and by Mundipharma Pharmaceutical Company, Pharmacogenetics 1996; 6: Basel, Switzerland. 15 Griese EU, Zanger UM, Brudermanns U, et al. Assessment We appreciate the excellent technical assistance of Mrs Erika of the predictive power of genotypes for the in-vivo catalytic Schneider and Mrs Anja Ziegler. function of CYP2D6 in a German population. Pharmacogenetics 1998; 8: Hofmann U, Fromm MF, Johnson S, Mikus G. References Simultaneous determination of dihydrocodeine and dihydromorphine in serum by gas chromatography-tandem 1 Rowell FJ, Seymour RA, Rawlins MD. Pharmacokinetics of mass spectrometry. J Chromatogr B Biomed Appl 1995; 663: intravenous and oral dihydrocodeine and its acid metabolites Eur J Clin Pharmacol 1983; 25: Kirkwood L, Nation RL, Somogyi AA. Glucuronidation of 2 Davies KN, Castleden CM, McBurney A, Jagger C. The dihydrocodeine by human liver microsomes and the effect of effect of ageing on the pharmacokinetics of dihydrocodeine. inhibitors. Clin Exp Pharmacol Physiol 1998; 25: Eur J Clin Pharmacol 1989; 37: Mikus G, Ulmer A, Mörike K, Hofmann U. Heroin 3 Fromm MF, Hofman U, Griese E-U, Mikus G. substitution therapy: Pharmacokinetics of dihydrocodeine. Dihydrocodeine: a new opioid substrate for the polymorphic Naunyn-Schmiedeberg s Arch Pharmacol 1998; 358(Suppl 2): P CYP2D6 in humans. Clin Pharmacol Ther 1995; 58: Chen ZR, Somogyi AA, Reynolds G, Bochner F. 4 Wotherspoon HA, Kenny GNC, McArdle CS. Analgesic Disposition and metabolism of codeine after single and efficacy of controlled release dihydrocodeine. Anaesthesia chronic doses in one poor and seven extensive metabolizers. 1991; 46: Br J Clin Pharmacol 1991; 31: Chen ZR, Somogyi AA, Bochner F. Polymorphic 2 Yue QY, Hasselström J, Svensson JO, Säwe O-demethylation of codeine. Lancet 1988; ii: J. Pharmacokinetics of codeine and ist metabolites in 6 Dayer P, Desmeules J, Leeman T, Striberni R. Bioactivation Caucasian healthy volunteers: comparisons between extensive of the narcotic drug codeine in humans is medicated by the and poor hydroxilators of debrisoquine. Br J Clin Pharmacol polymorphic monooxygenase catalysing debrisoquin 1991; 31: Blackwell Science Ltd Br J Clin Pharmacol, 48,