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 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.

Figures

Figure 1

Mean plasma (R)-methadone (•) and (S)-methadone (○) concentration-time profiles for 18 methadone maintenance patients. Data are represented as concentration normalized to a 70 mg rac-methadone dose. Error bars indicate s.d.

Figure 2

Mean plasma methadone (R)/(S) concentration ratio vs time profiles for 18 methadone maintenance patients. * Statistically significantly different from unity. Error bars indicate s.d. The y-axis has been truncated to enlarge the scale.

Figure 3

Relationship between dose and (a) (R)-methadone (•; r2 = 0.68, P < 0.0001) and (b) (S)-methadone(○r2 = 0.47, P = 0.002) AUCτSS. Dashed lines represent 95% confidence intervals.

Figure 4

Relationship between plasma α1-acid glycoprotein concentration and (a) plasma (R)-methadone (r2 = 0.31, P = 0.019) and (b) (S)-methadone (○; r2 = 0.30, P = 0.021) bound/unbound concentration ratio. Dashed lines represent 95% confidence intervals. The x-axis has been truncated to maintain a consistent scale.