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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.
Drug Metab Dispos 2008; 36(12):2547-55DM

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.

Authors+Show Affiliations

Pharmacogenomics and Drug Development Group, University of Sydney, NSW 2006, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -