BRAIN and NERVE Shinkei Kenkyu no Shinpo Volume 60, Issue 11 (November 2008)

Warfarin Resistance and Related Pharmacogenetic Information Harumi Takahashi 1 1Department of Pharmacotherapy,Meiji Pharmaceutical University Keyword: warfarin , resistance , CYP2C9 , VKORC1 , pharmacogenetics pp.1365-1371
Published Date 2008/11/1
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 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 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 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.

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BRAIN and NERVE-神経研究の進歩
60巻11号 (2008年11月)
電子版ISSN 1344-8129 印刷版ISSN 1881-6096 医学書院