Characterization of human cytochrome P450s involved in the bioactivation of clozapine.

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Dragovic S, Gunness P, Ingelman-Sundberg M, Vermeulen NP, Commandeur JN

Characterization of human cytochrome P450s involved in the bioactivation of clozapine.

Drug Metab Dispos. 2013 Mar;41(3):651-8. doi: 10.1124/dmd.112.050484. Epub 2013 Jan 7.

PubMed ID

23297297 [ View in PubMed

]

Abstract

Clozapine is known to cause hepatotoxicity in a small percentage of patients. Oxidative bioactivation to reactive intermediates by hepatic cytochrome P450s (P450s) has be proposed as a possible mechanism. However, in contrast to their role in formation of N-desmethylclozapine and clozapine N-oxide, the involvement of individual P450s in the bioactivation to reactive intermediates is much less well characterized. The results of the present study show that 7 of 14 recombinant human P450s were able to bioactivate clozapine to a glutathione-reactive nitrenium ion. CYP3A4 and CYP2D6 showed the highest specific activity. Enzyme kinetical characterization of these P450s showed comparable intrinsic clearance of bioactivation, implicating that CYP3A4 would be more important because of its higher hepatic expression, compared with CYP2D6. Inhibition experiments using pooled human liver microsomes confirmed the major role of CYP3A4 in hepatic bioactivation of clozapine. By studying bioactivation of clozapine in human liver microsomes from 100 different individuals, an 8-fold variability in bioactivation activity was observed. In two individuals bioactivation activity exceeded N-demethylation and N-oxidation activity. Quinidine did not show significant inhibition of bioactivation in any of these liver fractions, suggesting that CYP2D6 polymorphism is not an important factor in determining susceptibility to hepatotoxicity of clozapine. Therefore, interindividual differences and drug-drug interactions at the level of CYP3A4 might be factors determining exposure of hepatic tissue to reactive clozapine metabolites.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Clozapine	Cytochrome P450 2A6	Protein	Humans	No	Substrate	Details

Drug Reactions

Reaction
Clozapine DB00363 Cytochrome P450 3A4 Cytochrome P450 2C9 Cytochrome P450 2C19 Cytochrome P450 1A2 Cytochrome P450 2D6 Cytochrome P450 3A5 N-desmethylclozapine DBMET00100	Details
Clozapine DB00363 Cytochrome P450 3A4 Cytochrome P450 1A2 Dimethylaniline monooxygenase [N-oxide-forming] 3 Cytochrome P450 2C19 Cytochrome P450 3A5 Cytochrome P450 2D6 Cytochrome P450 2C9 Cytochrome P450 2E1 Clozapine N-oxide DBMET00101	Details

Drug Interactions

Drugs	Interaction
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Clozapine Peginterferon alfa-2b	The serum concentration of Clozapine can be increased when it is combined with Peginterferon alfa-2b.
Clozapine Vinorelbine	The serum concentration of Clozapine can be increased when it is combined with Vinorelbine.
Clozapine Sorafenib	The serum concentration of Clozapine can be increased when it is combined with Sorafenib.
Clozapine Cimetidine	The serum concentration of Clozapine can be increased when it is combined with Cimetidine.
Clozapine Vinblastine	The serum concentration of Clozapine can be increased when it is combined with Vinblastine.