title: Interindividual variation in relative CYP1A2/3A4 phenotype influences susceptibility of clozapine oxidation to cytochrome P450-specific inhibition in human hepatic microsomes.
abstract: The atypical antipsychotic drug clozapine (CLZ) is effective in a substantial number of patients who exhibit treatment-resistance to conventional agents. CYP1A2 is generally considered to be the major enzyme involved in the biotransformation of CLZ to its N-demethylated (norCLZ) and N-oxygenated (CLZ N-oxide) metabolites in liver, but several studies have also implicated CYP3A4. The present study assessed the interplay between these cytochrome P450s (P450s) in CLZ biotransformation in a panel of hepatic microsomal fractions from 14 individuals. The relative activity of P450s 1A2 and 3A4 in microsomes was found to be a major determinant of the relative susceptibility of norCLZ formation to inhibition by the P450-selective inhibitors fluvoxamine and ketoconazole. In contrast, the activity of CYP3A4 alone was correlated with the susceptibility of CLZ N-oxide formation to inhibition by these agents. These findings suggest that both P450s may be dominant CLZ oxidases in patients and that the relative activities of these enzymes may determine clearance pathways. In vivo assessment of CYP1A2 and CYP3A4 activities, perhaps by phenotyping approaches, could assist the optimization of CLZ dosage and minimize pharmacokinetic interactions with coadministered drugs.
authors.affiliation: Pharmacogenomics and Drug Development Group, University of Sydney, NSW 2006, Australia.
authors.forename: Wei V
authors.initials: WV
authors.lastname: Zhang
authors.forename: Fabrizio
authors.initials: F
authors.lastname: D'Esposito
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Edwards
authors.forename: Iqbal
authors.initials: I
authors.lastname: Ramzan
authors.forename: Michael
authors.initials: M
authors.lastname: Murray
mesh_terms: D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects / Q000235:genetics; D002384:Catalysis; D003024:Clozapine / Q000031:analogs & derivatives / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065702:Cytochrome P-450 CYP2B6; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014044:Tolbutamide / Q000378:metabolism
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; C058272:norclozapine; D013739:Testosterone; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D010105:Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C020066:dimethylaniline monooxygenase (N-oxide forming); D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C585599:CYP2B6 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; D003024:Clozapine; C079149:clozapine N-oxide; D016666:Fluvoxamine; D007654:Ketoconazole