Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine
Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine
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DOI：
10.1007/pl00005298
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发表时间：
1998-11-01
影响因子：
3.6
通讯作者：
Baker, GB
中科院分区：
文献类型：
--
作者：
Fang, J;Coutts, RT;Baker, GB
The atypical antipsychotic clozapine has been reported to be metabolised mainly to its N-oxide and N-demethylated products. Tn the present study, individual recombinant cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO) enzymes were used to elucidate which enzymes are responsible for these metabolic conversions. In vitro metabolism of clozapine was investigated using human CYP1A1, CYP1A2, CYP2C8, CYP2EI, CYP2C9-arg(144), CYP2C9-cys(144), CYP2C19, CYP2D6, CYP3A4, CYP3A5 and FMO3 supplemented with an NADPH generating system. Clozapine and its N-oxidation and N-demethylation metabolites were determined by an HPLC method with a Hypersil CN column and a UV detector. Of the enzymes investigated, CYP1A2, CYP3A4, CYP2D6, CYP2C8, CYP2C19 and, to a lesser extent, CYP2C9-cys, CYP2C9-arg and CYP3A5 were apparently involved in N-demethylation, while CYP1A2, CYP3A4, FMO3 and, to a lesser extent, CYP2C8, CYP2C19 and CYP3A5 were found to catalyse the formation of clozapine N-oxide. A bank of 16 human liver microsome preparations was investigated for ability to catalyze the production of clozapine N-oxide and N-desmethylclozapine. Attempts were made to correlate the rates of formation of these metabolites of clozapine to previously determined catalytic activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. At a clozapine concentration of 20 mu M, the rate of formation of clozapine N-oxide showed significant correlations with activities of CYP3A4 (P
