Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/14335
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients
Author: Foster, D.
Somogyi, A.
Dyer, K.
White, J.
Bochner, F.
Citation: British Journal of Clinical Pharmacology, 2000; 50(5):427-440
Publisher: Blackwell Publishing Ltd
Issue Date: 2000
ISSN: 0306-5251
1365-2125
Abstract: AIMS:To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population. METHODS:Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma alpha1-acid glycoprotein concentrations were quantified by radial immunoassay. RESULTS:(R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCtau_¿u¿ss (167%) was significantly (P < 0. 001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCtauss, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%. CONCLUSIONS:Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.
Keywords: Kidney; Humans; Substance-Related Disorders; Methadone; Pyrrolidines; Orosomucoid; Narcotics; Area Under Curve; Linear Models; Individuality; Protein Binding; Substrate Specificity; Stereoisomerism; Adult; Middle Aged; Female; Male
RMID: 0001000562
DOI: 10.1046/j.1365-2125.2000.00272.x
Appears in Collections:Pharmacology publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.