Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data

Abstract

The discovery of six distinct polymorphisms in the genetic sequence encoding for the cytochrome P450 2C9 (CYP2C9) protein has stimulated numerous investigations in an attempt to characterize their population distribution and metabolic activity. Since the CYP2C9*1, *2 and *3 alleles were discovered first, they have undergone more thorough investigation than the recently identified *4, *5 and *6 alleles. Population distribution data suggest that the variant *2 and *3 alleles are present in approximately 35% of Caucasian individuals; however, these alleles are significantly less prevalent in African-American and Asian populations. In-vitro data have consistently demonstrated that the CYP2C9*2 and *3 alleles are associated with significant reductions in intrinsic clearance of a variety of 2C9 substrates compared with CYP2C9*1; however, the degree of these reductions appear to be highly substrate-dependent. In addition, multiple in-vivo investigations and clinical case reports have associated genotypes expressing the CYP2C9*2 and *3 alleles with significant reductions in both the metabolism and daily dose requirements of selected CYP2C9 substrates. Individuals expressing these variant genotypes also appear to be significantly more susceptible to adverse events with the narrow therapeutic index agents warfarin and phenytoin, particularly during the initiation of therapy. These findings have subsequently raised numerous questions regarding the potential clinical utility of genotyping for CYP2C9 prior to initiation of therapy with these agents. However, further clinical investigations evaluating the metabolic consequences in individuals expressing the CYP2C9*2, *3, *4, *5, or *6 alleles are required before large-scale clinical genotyping can be recommended.