Genetic polymorphism of the human cytochrome P450 2C9 gene and its clinical significance.

Human cytochrome P450 2C9 (CYP2C9) accounts for approximately 20% of total hepatic CYP content and metabolizes approximately 15% clinically used drugs including S-warfarin, tolbutamide, phenytoin, losartan, diclofenac, and celecoxib. To date, there are at least 33 variants of CYP2C9 (1B through to 34) being identified. CYP2C92 and CYP2C93 differ from the wild-type CYP2C91 by a single point mutation: CYP2C92 is characterised by a 430C>T exchange in exon 3 resulting in an Arg144Cys amino acid substitution, whereas CYP2C93 shows an exchange of 1075A>C in exon 7 causing an Ile359Leu substitution in the catalytic site of the enzyme. CYP2C92 is frequent among Caucasians with approximately 1% of the population being homozygous carriers and 22% heterozygous. The corresponding figures for the CYP2C93 allele are 0.4% and 15%, respectively. Worldwide, a number of other variants have also to be considered. The CYP2C9 polymorphisms are relevant for the efficacy and adverse effects of numerous nonsteroidal anti-inflammatory agents, sulfonylurea antidiabetic drugs and, most critically, oral anticoagulants belonging to the class of vitamin K epoxide reductase inhibitors. Numerous clinical studies have shown that the CYP2C9 polymorphism should be considered in warfarin therapy and practical algorithms how to consider it in therapy are available. These studies have highlighted the importance of the CYP2C92 and *3 alleles. Warfarin has served as a practical example of how pharmacogenetics can be utilized to achieve maximum efficacy and minimum toxicity. Polymorphisms in CYP2C9 have the potential to affect the toxicity of CYP2C9 drugs with somewhat lower therapeutic indices such as warfarin, phenytoin, and certain antidiabetic drugs. CYP2C9 is one of the clinically significant drug metabolising enzymes that demonstrates genetic variants with significant phenotype and clinical outcomes. Genetic testing of CYP2C9 is expected to have a role in predicting drug clearance and implementing individualized pharmacotherapy. Prospective clinical studies with large samples are required to establish gene-dose and gene-effect relatiohsips for CYP2C9.