３．WarfarinとCYP2C9，VKORC1遺伝子多型

抄録

Warfarin is the mainstay of anticoagulation therapy, worldwide. Its clinical use, however, is complicated by the fact that it has a narrow therapeutic index with potential bleeding complications. The dosage requirement of warfarin to produce therapeutic anticoagulation varies widely among patients. Recently genetic factors such as the CYP2C9 and VKORC1 genes have been demonstrated to be determinants of warfarin response. CYP2C9 is the enzyme primarily responsible for the metabolic clearance of the S-enantiomer of warfarin. VKOR is the target protein of warfarin which recycles the reduced form of vitamin K, an essential cofactor in the formation of the vitamin K-dependent clotting factors. There is strong evidence to support an association between these genetic variants and therapeutic doses of warfarin. On the basis of these observations, the Food and Drug Administration (FDA) approved a labeling change for warfarin that includes the genetic information of VKORC1 and CYP2C9 as factors influencing inter-individual variability in warfarin dosing. The package insert as of August 2007 states that “lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes.” The FDA also approved clinical tests for these genetic variants. However, at present, a validated dosing algorithm, evidence of the clinical utility of genotyping and a reliable economic analysis are not availabie to recommend routine CYP2C9 and VKORC1 testing in every patient before the initiation of warfarin. The results of several randomized prospective controlled trials conducted to test the impact of genotype-guided warfarin dosing in Caucasian and Asian patients are shown in this review.