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

Background: The pharmacokinetics and dynamics of methadone are characterize d 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-m ethadone orally. The con centrations of methadone's enantiomers in plasma a nd urine were monitored for 96 hours. Vital signs, blood biochemical parame ters, and pupillary diameter were monitored frequently during this period. Cytochrome P450 3A (CY-P3A) activity and alpha (1)-acid glycoprotein (alpha (1)-AGP) concentrations and phenotypes were determined. Pharmacokinetic an d pharmacodynamic modeling was used to assess the influence of the above-me ntioned 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 th e interindividual variability in modeled pharmacokinetic parameters being e xplained by their individual variability in CYP3A activity, the cumulative amount of the main CYP3A4 metabolite, 2-ethylidene-1,5-dimethyl-3,3-dipheny lpyrolidine, excreted in the urine, the fraction unbound in plasma, and the alpha (1)-AGP orosomucoid 2 (ORM2) variant plasma concentration. S-Methado ne showed an idiosyncratic distribution with largely unpredictable pharmaco kinetics. Pupillary constriction response was highly variable between indiv iduals. Conclusions: The disposition of the active enantiomer, R-methadone, ran be predicted in part by CYP3A activity and protein binding to alpha (1)-AGP (O RM2), whereas S-methadone disposition is not well explained by the factors examined in this study. Central nervous system effects were difficult to in terpret on the basis of plasma R-methadone pharmacokinetics.