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Interindividual variation in relative CYP1A2/3A4 phenotype influences susceptibility of clozapine oxidation to cytochrome P450-specific inhibition in human hepatic microsomes.

Abstract

The atypical antipsychotic drug clozapine (CLZ) is effective in a substantial number of patients who exhibit treatment-resistance to conventional agents. CYP1A2 is generally considered to be the major enzyme involved in the biotransformation of CLZ to its N-demethylated (norCLZ) and N-oxygenated (CLZ N-oxide) metabolites in liver, but several studies have also implicated CYP3A4. The present study assessed the interplay between these cytochrome P450s (P450s) in CLZ biotransformation in a panel of hepatic microsomal fractions from 14 individuals. The relative activity of P450s 1A2 and 3A4 in microsomes was found to be a major determinant of the relative susceptibility of norCLZ formation to inhibition by the P450-selective inhibitors fluvoxamine and ketoconazole. In contrast, the activity of CYP3A4 alone was correlated with the susceptibility of CLZ N-oxide formation to inhibition by these agents. These findings suggest that both P450s may be dominant CLZ oxidases in patients and that the relative activities of these enzymes may determine clearance pathways. In vivo assessment of CYP1A2 and CYP3A4 activities, perhaps by phenotyping approaches, could assist the optimization of CLZ dosage and minimize pharmacokinetic interactions with coadministered drugs.

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  • Authors+Show Affiliations

    ,

    Pharmacogenomics and Drug Development Group, University of Sydney, NSW 2006, Australia.

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    MeSH

    Alleles
    Aryl Hydrocarbon Hydroxylases
    Biotransformation
    Catalysis
    Clozapine
    Cytochrome P-450 CYP1A1
    Cytochrome P-450 CYP1A2
    Cytochrome P-450 CYP1A2 Inhibitors
    Cytochrome P-450 CYP2B6
    Cytochrome P-450 CYP2C9
    Cytochrome P-450 CYP3A
    Cytochrome P-450 CYP3A Inhibitors
    Cytochrome P-450 Enzyme Inhibitors
    Cytochrome P-450 Enzyme System
    Dextromethorphan
    Enzyme Inhibitors
    Fluvoxamine
    Humans
    Isoenzymes
    Ketoconazole
    Kinetics
    Microsomes, Liver
    Oxidation-Reduction
    Oxidoreductases, N-Demethylating
    Oxygenases
    Recombinant Proteins
    Testosterone
    Tolbutamide

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    18809730

    Citation

    Zhang, Wei V., et al. "Interindividual Variation in Relative CYP1A2/3A4 Phenotype Influences Susceptibility of Clozapine Oxidation to Cytochrome P450-specific Inhibition in Human Hepatic Microsomes." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 36, no. 12, 2008, pp. 2547-55.
    Zhang WV, D'Esposito F, Edwards RJ, et al. Interindividual variation in relative CYP1A2/3A4 phenotype influences susceptibility of clozapine oxidation to cytochrome P450-specific inhibition in human hepatic microsomes. Drug Metab Dispos. 2008;36(12):2547-55.
    Zhang, W. V., D'Esposito, F., Edwards, R. J., Ramzan, I., & Murray, M. (2008). Interindividual variation in relative CYP1A2/3A4 phenotype influences susceptibility of clozapine oxidation to cytochrome P450-specific inhibition in human hepatic microsomes. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 36(12), pp. 2547-55. doi:10.1124/dmd.108.023671.
    Zhang WV, et al. Interindividual Variation in Relative CYP1A2/3A4 Phenotype Influences Susceptibility of Clozapine Oxidation to Cytochrome P450-specific Inhibition in Human Hepatic Microsomes. Drug Metab Dispos. 2008;36(12):2547-55. PubMed PMID: 18809730.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Interindividual variation in relative CYP1A2/3A4 phenotype influences susceptibility of clozapine oxidation to cytochrome P450-specific inhibition in human hepatic microsomes. AU - Zhang,Wei V, AU - D'Esposito,Fabrizio, AU - Edwards,Robert J, AU - Ramzan,Iqbal, AU - Murray,Michael, Y1 - 2008/09/22/ PY - 2008/9/24/pubmed PY - 2009/6/6/medline PY - 2008/9/24/entrez SP - 2547 EP - 55 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 36 IS - 12 N2 - The atypical antipsychotic drug clozapine (CLZ) is effective in a substantial number of patients who exhibit treatment-resistance to conventional agents. CYP1A2 is generally considered to be the major enzyme involved in the biotransformation of CLZ to its N-demethylated (norCLZ) and N-oxygenated (CLZ N-oxide) metabolites in liver, but several studies have also implicated CYP3A4. The present study assessed the interplay between these cytochrome P450s (P450s) in CLZ biotransformation in a panel of hepatic microsomal fractions from 14 individuals. The relative activity of P450s 1A2 and 3A4 in microsomes was found to be a major determinant of the relative susceptibility of norCLZ formation to inhibition by the P450-selective inhibitors fluvoxamine and ketoconazole. In contrast, the activity of CYP3A4 alone was correlated with the susceptibility of CLZ N-oxide formation to inhibition by these agents. These findings suggest that both P450s may be dominant CLZ oxidases in patients and that the relative activities of these enzymes may determine clearance pathways. In vivo assessment of CYP1A2 and CYP3A4 activities, perhaps by phenotyping approaches, could assist the optimization of CLZ dosage and minimize pharmacokinetic interactions with coadministered drugs. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/18809730/Interindividual_variation_in_relative_CYP1A2/3A4_phenotype_influences_susceptibility_of_clozapine_oxidation_to_cytochrome_P450_specific_inhibition_in_human_hepatic_microsomes_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18809730 DB - PRIME DP - Unbound Medicine ER -