[Warfarin resistance and related pharmacogenetic information].
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. VKORC1 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 a therapeutic dose 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 interindividual 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 has also approved clinical tests for these genetic variants. However, at this time, validated dosing algorithm and evidence to support the clinical utility of genotyping and reliable economic analysis are lacking to recommend for routine CYP2C9 and VKORC1 testing in every patiens before the initiation of warfarin therapy. In this review, we present the results of several prospective randomised controlled trials conducted to test the impact of genotype-guided warfarin dosing in Caucasian and Asian patients initiating warfarin.
Takahashi
Harumi
H
Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose-shi, Tokyo 204-8588, Japan.
D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004351:Drug Resistance / Q000235:genetics; D005838:Genotype; D006801:Humans; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000235:genetics; D009154:Mutation; D010597:Pharmacogenetics; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases