In vitro and in vivo evaluation of the inhibition potential of risperidone toward clozapine biotransformation

center dot The clozapine (CLZ)-risperidone (RISP) combination is effective in schizophrenic patients but may lead to elevated plasma CLZ concentrations and adverse effects. center dot Reports of potential inhibitory effects of RISP on cytochrome P450 (CYP)-dependent CLZ oxidation have been inconsistent. center dot It has been suggested that variations in expression of CLZ/RISP oxidases, such as CYPs 1A2, 2D6 and 3A4, may influence inhibitory interactions. WHAT THIS STUDY ADDS center dot Inhibition of CLZ biotransformation by RISP was assessed in microsomal fractions that expressed varying amounts of CYPs 1A2, 2D6 and 3A4. center dot RISP did not inhibit the formation of major oxidized CLZ metabolites, regardless of the CYP expression profile; findings from an in vivo study in patients were consistent with this finding. center dot Pharmacokinetic interactions due to the RISP-CLZ combination are unlikely to involve CYPs. AIMS To study the impact of risperidone (RISP) on clozapine (CLZ) biotransformation in vitro in microsomal fractions containing varying expression of CYP oxidases and in vivo in patients. METHODS Human liver microsomes (n = 11) were assessed for expression of CYPs 1A2, 2D6 and 3A4, because these enzymes mediate RISP and CLZ oxidation. Inhibition of CLZ oxidation by RISP was assessed. Plasma CLZ elimination was estimated in patients with schizophrenia who received either CLZ alone or the CLZ-RISP combination (n = 10 per group). RESULTS (i) The CYP3A4 and CYP1A2 inhibitors ketoconazole and fluvoxamine inhibited CLZ oxidation to varying extents in individual microsomal fractions. (ii) RISP did not inhibit CLZ oxidation, regardless of variations in CYP expression. (iii) RISP co-administration did not impair CLZ clearance. CONCLUSIONS No evidence was found for CYP-mediated inhibitory or pharmacokinetic interactions between RISP and CLZ. Occasional literature reports of such interactions may involve other pathways that participate in CLZ disposition.