Received for publication May 2, 2006.
Revised September 6, 2006.
Accepted for publication September 8, 2006.

CYP2C9 Inhibition: Impact of Probe Selection and Pharmacogenetics on In Vitro Inhibition Profiles

Abstract

Drug-drug interactions may cause serious adverse events in the clinical setting and the cytochromes P450 are the enzyme system most often implicated in these interactions. Cytochrome P450 2C is the second most abundant sub-family of P450 enzymes and is responsible for metabolism of almost twenty percent of currently marketed drugs. The most abundant isoform of this sub-family is CYP2C9, which is the major clearance pathway for the low therapeutic index drugs warfarin and phenytoin. Considering the importance of CYP2C9 to drug-drug interactions, the in vitro-in vivo extrapolation of drug-drug interactions for CYP2C9 may be confounded by the presence of polymorphic variants and the possibility of multiple binding regions within the CYP2C9 active site, leading to the potential for genotype and substrate-dependent inhibition. To address the issues of genotype dependent enzyme inhibition as well as probe substrate correlations, the inhibitory potency (Ki) of twenty-eight effector molecules was assessed with five commonly used probes of CYP2C9 in both the CYP2C9.1 and CYP2C9.3 proteins. The inhibition of CYP2C9.1 and CYP2C9.3 by the battery of inhibitors with five substrate probes demonstrated not only differential inhibition potency between the two genotypes but also across substrate probes. Furthermore, the substrate probes fell into three distinct classes depending on genotype suggesting that multiple probes may be needed to fully assess inhibition of CYP2C9 in vitro. Thus, both genotype and choice of probe substrate must be considered when attempting to predict potential CYP2C9 drug-drug interactions from in vitro data.

Key words: CYP inhibition, CYP2C, cytochrome P450, drug interactions, drug-drug interactions, pharmacogenetics

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