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Titolo:
ELUCIDATION OF INDIVIDUAL CYTOCHROME-P450 ENZYMES INVOLVED IN THE METABOLISM OF CLOZAPINE
Autore:
FANG J; COUTTS RT; MCKENNA KF; BAKER GB;
Indirizzi:
UNIV ALBERTA,DEPT PSYCHIAT,NEUROCHEM RES UNIT EDMONTON AB T6G 2R7 CANADA
Titolo Testata:
Naunyn-Schmiedeberg's archives of pharmacology
fascicolo: 5, volume: 358, anno: 1998,
pagine: 592 - 599
SICI:
0028-1298(1998)358:5<592:EOICEI>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
MULTIPLE-DOSE PHARMACOKINETICS; INDUCED AGRANULOCYTOSIS; SCHIZOPHRENIC-PATIENTS; N-DESMETHYLCLOZAPINE; RISK-FACTORS; SERUM; CARBAMAZEPINE; DISPOSITION; FLUVOXAMINE; FLUOXETINE;
Keywords:
CLOZAPINE; CYTOCHROME P450; FLAVIN-CONTAINING MONOOXYGENASE; HUMAN LIVER; DRUG METABOLISM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
32
Recensione:
Indirizzi per estratti:
Citazione:
J. Fang et al., "ELUCIDATION OF INDIVIDUAL CYTOCHROME-P450 ENZYMES INVOLVED IN THE METABOLISM OF CLOZAPINE", Naunyn-Schmiedeberg's archives of pharmacology, 358(5), 1998, pp. 592-599

Abstract

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 ofclozapine 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 itsN-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 offormation of these metabolites of clozapine to previously determined catalytic activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Ata clozapine concentration of 20 mu M, the rate of formation of clozapine N-oxide showed significant correlations with activities of CYP3A4 (P<0.01) and CYP1A2 (P<0.05). The formation of N-desmethylclozapine exhibited significant correlations with CYP1A2 (P<0.01) and CYP3A4 (P<0.01). Similar correlations were observed when the clozapine concentration was increased to 300 mu M except that the formation of clozapine N-oxide no longer correlated with CYP1A2 activity. It can be seen from these results that although some recombinant enzymes individually are capable of metabolising clozapine, the activities of several of these enzymes did not correlate with clozapine metabolism when mixtures of the enzymes are used. By combining the results of the current study and those reported in the literature, it is proposed that CYP3A4 and FMO3 are primarily responsible for the production of clozapine N-oxide, andCYP3A4 and CYP1A2 are primarily responsible for the formation of N-desmethylclozapine. The present study demonstrates the importance of theuse of multiple techniques for the elucidation of the enzymes involved in the metabolism of certain drugs.

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Documento generato il 26/01/20 alle ore 00:45:09