Steady‐state pharmacokinetics of (R)‐ and (S)‐methadone in methadone maintenance patients

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 ultra®ltration, and plasma a 1 -acid glycoprotein concentrations were quanti®ed by radial immunoassay. Results (R)-methadone had a signi®cantly (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 signi®cantly (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 signi®cantly (P<0.01) lower than for (S)-methadone, while AUC ss q u (167%) was signi®cantly (P<0.001) greater. There were no signi®cant (P>0.2) differences between the methadone enantiomers for AUC ss q , steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted signi®cantly (P<0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coef®cients 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 signi®cant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokineticpharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.

Pharmacokinetic Interaction between Voriconazole and Methadone at Steady State in Patients on Methadone Therapy

“…The area under the plasma concentration-time curve (AUC) during the dosing interval () (AUC from 0 to 24 h [AUC 0-24 ] for methadone and AUC 0-12 for voriconazole and the N-oxide metabolite) was estimated using linear/log-trapezoidal approximation. The approximate linearity of methadone steady-state pharmacokinetics at daily doses ranging from 7.5 mg to 130 mg was demonstrated previously (13). For the purpose of presenting mean pharmacokinetic profiles and mean parameter values at a given dose, the methadone concentrations were dose normalized to a 100-mg equivalent dose.…”

“…These calculations were based on the intersubject coefficient of variation (55%) of the steady-state AUC 0-24 for (R)-methadone (13).…”

Le dépistage immunochimique des médicaments substitutifs de l'héroïne et autres opioïdes

“…Sa pharmacocinétique présente une forte variabilité interindividuelle, d'une part du fait qu'elle est le substrat de la glycoprotéine P (P-gP) [8], et d'autre part parce qu'elle subit un métabolisme par le cytochrome 3A4, à l'origine d'une N-déméthylation suivie d'une cyclisation pour aboutir au mé-tabolite majeur de la méthadone, l'EDDP. C'est essentiellement la forme (S) qui subit le métabolisme, la forme (R) étant principalement éliminée sous forme inchangée [9]. Cette éli-mination se fait pour un tiers dans les urines sous forme inchangée, un tiers dans les urines sous forme d'EDDP et un tiers dans les fécès sous forme d'EDDP.…”

High Frequency of CYP3A4*1B among Opiate Dependent Patients in Malaysia

“…It is a vital public health strategy for HIV/AIDS risk reduction [1]. Variability in methadone clearance, susceptibility to drug interactions, and a long elimination half-life can however be major impediments to optimal methadone use [2,3]. In in vitro drug metabolism studies, CYP3A4 has been implicated in methadone metabolism [4].…”

“…In in vitro drug metabolism studies, CYP3A4 has been implicated in methadone metabolism [4]. Authors have suggested dosing guidelines for methadone and warned about the potential for CYP3A4-mediated interactions and suggested the need to adjust doses accordingly [2,3,[5][6][7][8][9][10][11].…”