PMID: 15349140Sep 7, 2004Paper

CYP2C9 genotype as a predictor of drug disposition in humans

Methods and Findings in Experimental and Clinical Pharmacology
Craig R Lee

Abstract

Discovery of genetic polymorphisms in CYP2C9 has stimulated numerous in vitro and in vivo studies evaluating the influence of CYP2C9 genotype on metabolic activity and drug disposition. CYP2C9*2 (Arg144Cys) and *3 (Ile359Leu) have been the most widely studied alleles. They are present in approximately 10-15% and 5-10% of white populations, respectively, and are even less frequent in black and Asian populations. The CYP2C9*2 and *3 alleles have been consistently associated with lower intrinsic clearance compared with CYP2C9*1 in vitro; however, the magnitude of these differences appears to be highly substrate-specific. In addition, multiple human studies have demonstrated significant associations between CYP2C9 genotype and the disposition of substrates such as warfarin, phenytoin and various sulfonylureas, angiotensin II receptor blockers and non-steroidal antiinflammatory agents. Individuals carrying the CYP2C9*2 and *3 alleles also have lower warfarin and phenytoin daily dose requirements, and appear more susceptible to adverse events during the initiation of therapy. Collectively, these findings suggest that CYP2C9 genotype-guided dosing may be clinically useful and warrants prospective investigation.

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