Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate

Background The pharmacokinetics and dynamics of methadone are characterized by high interindividual variability. This study aimed to examine a number of factors that may contribute to this variability. Methods Eight healthy drug‐free women were administered 0.2 mg/kg of R , S ‐methadone orally. The concentrations of methadone's enantiomers in plasma and urine were monitored for 96 hours. Vital signs, blood biochemical parameters, and pupillary diameter were monitored frequently during this period. Cytochrome P450 3A (CYP3A) activity and α 1 ‐acid glycoprotein (α 1 ‐AGP) concentrations and phenotypes were determined. Pharmacokinetic and pharmacodynamic modeling was used to assess the influence of the above‐mentioned covariables on methadone enantiomer disposition and actions. Results The pharmacokinetic profile of the active enantiomer of methadone, R ‐methadone, showed a relatively normal distribution with 38% to 90% of the interindividual variability in modeled pharmacokinetic parameters being explained by their individual variability in CYP3A activity, the cumulative amount of the main CYP3A4 metabolite, 2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrolidine, excreted in the urine, the fraction unbound in plasma, and the α 1 ‐AGP orosomucoid 2 (ORM2) variant plasma concentration. S ‐Methadone showed an idiosyncratic distribution with largely unpredictable pharmacokinetics. Pupillary constriction response was highly variable between individuals. Conclusions The disposition of the active enantiomer, R ‐methadone, can be predicted in part by CYP3A activity and protein binding to α 1 ‐AGP (ORM2), whereas S ‐methadone disposition is not well explained by the factors examined in this study. Central nervous system effects were difficult to interpret on the basis of plasma R ‐methadone pharmacokinetics. Clinical Pharmacology & Therapeutics (2001) 70 , 48–57; doi: 10.1067/mcp.2001.116793