In vitro and in vivo evaluation of the inhibition potential of risperidone toward clozapine biotransformation.
OBJECTIVE
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.
Chetty
Manoranjenni
M
Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia.
d'Esposito
Fabrizio
F
Zhang
Wei V
WV
Glen
John
J
Dore
Glenys
G
Stankovic
Zvijezdana
Z
Edwards
Robert J
RJ
Ramzan
Iqbal
I
Murray
Michael
M
D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001711:Biotransformation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000037:antagonists & inhibitors*; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D008875:Middle Aged; D018967:Risperidone / Q000494:pharmacology*; D012559:Schizophrenia / Q000188:drug therapy*; D055815:Young Adult
D014150:Antipsychotic Agents; D004338:Drug Combinations; D003577:Cytochrome P-450 Enzyme System; D003024:Clozapine; D018967:Risperidone; D016666:Fluvoxamine; D007654:Ketoconazole