title: CYP2C9 genotype as a predictor of drug disposition in humans.
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.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. craig_lee@unc.edu
authors.forename: C R
authors.initials: CR
authors.lastname: Lee
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011237:Predictive Value of Tests; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D004364:Pharmaceutical Preparations; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases