CYP2C9 genotype as a predictor of drug disposition in humans

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.