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Research ArticleArticle

Characterization of Human Cytochrome P450s Involved in the Bioactivation of Clozapine

Sanja Dragovic, Patrina Gunness, Magnus Ingelman-Sundberg, Nico P.E. Vermeulen and Jan N. M. Commandeur
Drug Metabolism and Disposition March 2013, 41 (3) 651-658; DOI: https://doi.org/10.1124/dmd.112.050484
Sanja Dragovic
Division of Molecular Toxicology, Leiden/Amsterdam Center for Drug Research, Faculty of Sciences, Vrije Universiteit, Amsterdam, The Netherlands (S.D., N.P.E.V., J.N.M.C.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (P.G., M.I.-S.)
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Patrina Gunness
Division of Molecular Toxicology, Leiden/Amsterdam Center for Drug Research, Faculty of Sciences, Vrije Universiteit, Amsterdam, The Netherlands (S.D., N.P.E.V., J.N.M.C.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (P.G., M.I.-S.)
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Magnus Ingelman-Sundberg
Division of Molecular Toxicology, Leiden/Amsterdam Center for Drug Research, Faculty of Sciences, Vrije Universiteit, Amsterdam, The Netherlands (S.D., N.P.E.V., J.N.M.C.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (P.G., M.I.-S.)
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Nico P.E. Vermeulen
Division of Molecular Toxicology, Leiden/Amsterdam Center for Drug Research, Faculty of Sciences, Vrije Universiteit, Amsterdam, The Netherlands (S.D., N.P.E.V., J.N.M.C.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (P.G., M.I.-S.)
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Jan N. M. Commandeur
Division of Molecular Toxicology, Leiden/Amsterdam Center for Drug Research, Faculty of Sciences, Vrije Universiteit, Amsterdam, The Netherlands (S.D., N.P.E.V., J.N.M.C.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (P.G., M.I.-S.)
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This article has a correction. Please see:

  • Correction to “Characterization of Human Cytochrome P450s Involved in the Bioactivation of Clozapine” - April 01, 2013

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.

Footnotes

  • This research was performed within the framework of project D3-201 of the Dutch Top Institute Pharma.

  • dx.doi.org/10.1124/dmd.112.050484.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Received December 2, 2012.
  • Accepted January 3, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (3)
Drug Metabolism and Disposition
Vol. 41, Issue 3
1 Mar 2013
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Research ArticleArticle

Bioactivation of Clozapine by Human P450s

Sanja Dragovic, Patrina Gunness, Magnus Ingelman-Sundberg, Nico P.E. Vermeulen and Jan N. M. Commandeur
Drug Metabolism and Disposition March 1, 2013, 41 (3) 651-658; DOI: https://doi.org/10.1124/dmd.112.050484

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Research ArticleArticle

Bioactivation of Clozapine by Human P450s

Sanja Dragovic, Patrina Gunness, Magnus Ingelman-Sundberg, Nico P.E. Vermeulen and Jan N. M. Commandeur
Drug Metabolism and Disposition March 1, 2013, 41 (3) 651-658; DOI: https://doi.org/10.1124/dmd.112.050484
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