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

Aims To investigate the steady-state pharmacokinetics of (R)- and (S)-metha done in a methadone maintenance population. Methods Eighteen patients recruited from a public methadone maintenance pro gram underwent an interdosing interval pharmacokinetic study. Plasma and ur ine samples were collected and analysed for methadone and its major metabol ite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma alpha (1)-acid glycoprotein concentrations were quantified by radial immunoassay. Results (R)-methadone had a significantly (P < 0.05) greater unbound fracti on (mean 173%) and total renal clearance (182%) compared with (S)-methadone , while maximum measured plasma concentrations (83%) and apparent partial c learance of methadone to EDDP (76%) were significantly (P < 0.001) lower. W hen protein binding was considered (R)-methadone plasma clearance of the un bound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUC(tauu )(ss) (167%) was significantly (P < 0.001) greater. There were no significa nt (P > 0.2) differences between the methadone enantiomers for AUC(tau)(ss) , steady-state plasma clearance, trough plasma concentrations and unbound r enal clearance. Patients excreted significantly (P < 0.0001) more (R)-metha done and (S)-EDDP than the corresponding enantiomers. Considerable interind ividual variability was observed for the pharmacokinetic parameters, with c oefficients of variation of up to 70%. Conclusions Steady-state pharmacokinetics of unbound methadone are stereose lective, and there is large interindividual variability consistent with CYP 3A4 mediated metabolism to the major metabolite EDDP; the variability did n ot obscure a significant dose-plasma concentration relationship. Stereosele ctive differences in the pharmacokinetics of methadone may have important i mplications for pharmacokinetic-pharmacodynamic modelling but is unlikely t o be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.