title: A PET study of D2 and 5-HT2 receptor occupancy induced by risperidone in poor metabolizers of debrisoquin and risperidone.
abstract: The hydroxylation of the new antipsychotic drug risperidone to its main, active metabolite 9-hydroxyrisperidone is catalyzed by the hepatic cytochrome P450 enzyme CYP2D6, and cosegregates with the polymorphic hydroxylation of debrisoquin. We have previously examined central D2 dopamine and 5-HT2 receptor occupancy after 1 mg risperidone orally in three healthy subjects who were extensive metabolizers (EM) of debrisoquin, using positron emission tomography and the radioligands [11C]raclopride and [11C]NMSP. In this study, the same experimental design was repeated in two healthy poor metabolizers (PM) of debrisoquin to compare the D2 and 5-HT2 receptor occupancy induced by risperidone in EM and PM. The two PM had much higher plasma concentrations and longer elimination half-lives of risperidone than the three EM. Plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone partly overlapped among the EM and PM. D2 receptor occupancy was 50% and 54% in the two PM, as compared to 40%, 43% and 55% in the EM. 5-HT2 receptor occupancy was 63% and 73%, as compared to 45%, 56% and 68% in the EM. These findings support the view that the active 9-hydroxyl metabolite of risperidone contributes to the in vivo effects of risperidone in humans, and thus partly counterbalances the marked variability in the disposition of risperidone.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Nyberg
authors.forename: M L
authors.initials: ML
authors.lastname: Dahl
authors.forename: C
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003647:Debrisoquin / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007555:Isoxazoles / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011954:Receptors, Dopamine / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D018967:Risperidone; D014055:Tomography, Emission-Computed
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D010880:Piperidines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D018967:Risperidone; D003647:Debrisoquin