Received for publication August 4, 2008.
Revised September 18, 2008.
Accepted for publication September 19, 2008.

Inter-Individual Variation in Relative CYP1A2/3A4 Phenotype Influences Susceptibility of Clozapine Oxidation to CYP-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 CYPs in CLZ biotransformation in a panel of hepatic microsomal fractions from fourteen individuals. The relative activity of CYPs 1A2 and 3A4 in microsomes was found to be a major determinant of the relative susceptibility of norCLZ formation to inhibition by the CYP-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 CYPs 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 minimise pharmacokinetic interactions with coadministered drugs.

Key words: CYP expression, cytochrome P450 function, drug interactions, enzyme inhibitors, human CYP enzymes, liver microsomes, pharmacogenetics