PHARMACOKINETICS OF DEXTROMETHORPHAN AND METABOLITES IN HUMANS - INFLUENCE OF THE CYPBDB PHENOTYPE AND QUINIDINE INHIBITION

Dextromethorphan is primarily metabolized to dextrorphan by cytochrome P450 2D6 (CYP2D6), a genetically polymorphic enzyme in humans. Dextro rphan is an active metabolite that produces phencyclidine-like behavio ral effects in animals and exhibits anticonvulsant and neuroprotective properties in a variety of experimental models. In these studies, we examined the effects of CYP2D6 phenotype and quinidine inhibition on t he pharmacokinetics of dextromethorphan and its metabolites in humans. After a single oral dose of dextromethorphan HBr (30 mg), the major m etabolites in the plasma of extensive metabolizers (N = 5) were conjug ated dextrorphan and conjugated 3-hydroxymorphinan. Free dextrorphan c oncentrations were about 100-fold less than the conjugated dextrorphan , and dextromethorphan was not detectable. Pretreatment of these subje cts with 100 mg of quinidine, a selective inhibitor of CYP2D6, signifi cantly suppressed the formation of dextrorphan and elevated the concen trations of dextromethorphan (t(1/2), 16.4 hours). In poor metabolizer s (N = 4) given the same dose, dextromethorphan was the major componen t in the plasma with a t(1/2) of 29.5 hours. Present at Concentrations 5- to 10-fold less were conjugated dextrorphan and the other two meta bolites. Urinary recovery studies indicated that the inhibition by qui nidine was reversible and that the elimination of dextromethorphan pri marily depends on CYP2D6 activity rather than renal elimination. These data demonstrated that the CYP2D6 phenotype and the concurrent admini stration of quinidine significantly affect the disposition of dextrome thorphan and the formation of the active metabolite dextrorphan and ar e important factors to be considered in studies of the pharmacologic a nd behavioral effects of dextromethorphan.