{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T05:14:22Z","timestamp":1739250862600,"version":"3.37.0"},"reference-count":24,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2009,6,30]],"date-time":"2009-06-30T00:00:00Z","timestamp":1246320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2009,10]]},"abstract":"<jats:sec><jats:label\/><jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003The clozapine (CLZ)\u2013risperidone (RISP) combination is effective in schizophrenic patients but may lead to elevated plasma CLZ concentrations and adverse effects.<\/jats:p><jats:p>\u2022\u2003Reports of potential inhibitory effects of RISP on cytochrome P450 (CYP)\u2010dependent CLZ oxidation have been inconsistent.<\/jats:p><jats:p>\u2022\u2003It has been suggested that variations in expression of CLZ\/RISP oxidases, such as CYPs 1A2, 2D6 and 3A4, may influence inhibitory interactions.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Inhibition of CLZ biotransformation by RISP was assessed in microsomal fractions that expressed varying amounts of CYPs 1A2, 2D6 and 3A4.<\/jats:p><jats:p>\u2022\u2003RISP did not inhibit the formation of major oxidized CLZ metabolites, regardless of the CYP expression profile; findings from an<jats:italic>in vivo<\/jats:italic>study in patients were consistent with this finding.<\/jats:p><jats:p>\u2022\u2003Pharmacokinetic interactions due to the RISP\u2013CLZ combination are unlikely to involve CYPs.<\/jats:p><\/jats:sec><jats:sec><jats:title>AIMS<\/jats:title><jats:p>To study the impact of risperidone (RISP) on clozapine (CLZ) biotransformation<jats:italic>in vitro<\/jats:italic>in microsomal fractions containing varying expression of CYP oxidases and<jats:italic>in vivo<\/jats:italic>in patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Human liver microsomes (<jats:italic>n<\/jats:italic>= 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\u2013RISP combination (<jats:italic>n<\/jats:italic>= 10 per group).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>(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\u2010administration did not impair CLZ clearance.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>No evidence was found for CYP\u2010mediated inhibitory or pharmacokinetic interactions between RISP and CLZ. 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