The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine

摘要: Aims Clozapine (CLZ), an atypical neuroleptic with a high risk of causing agranulocytosis, is metabolized in the liver to desmethylclozapine (DCLZ) and clozapine N-oxide (CLZ-NO). This study investigated involvement different CYP isoforms formation these two metabolites. Methods Human microsomal incubations, chemical inhibitors, specific antibodies, cytochrome P450 expression systems were used. Results Km Vmax values determined human microsomes lower for demethylation (61±21 μm, 159±42 pmol min−1 mg protein−1 mean±s.d.; n=4), than N-oxidation CLZ (308±1.5 μm, 456±167pmol min−1 mg protein−1; n=3). Formation DCLZ was inhibited by fluvoxamine (53±28% at 10 μm ), triacetyloleandomycin (33±15% ketoconazole (51±28% 2 μm ) antibodies against CYP1A2 CYP3A4. CLZ-NO (34±16% 10 μm ) (51±13% 2 μm ), There significant correlation between CYP3A content from 15 livers (r=0.67; P=0.04). A but not coefficient found (r=0.59; P=0.09). Using it shown that CYP3A4 formed CLZ-NO. Km system compared both metabolic reactions. Conclusions It concluded are involved CLZ. Close monitoring plasma levels recommended patients treated same time other drugs affecting enzymes.