Warfarin Enantiomers Pharmacokinetics by CYP2C19

Abstract

Warfarin, a coumarin vitamin K antagonist, is the most widely prescribed anticoagulant agent for the control and prevention of atrial fibrillation-related thrombus formation, stroke, and arterial and venous thrombembolism (Hirsh J et al., 1998). The recommend warfarin therapy consists of the lowest dose required to maintain the target international normalized ratio (INR) because of the drug’s narrow therapeutic window. However, there can be a 20fold difference in the dose required by patients to achieve this target INR. It is well known that cytochrome P450 (CYP), predominantly CYP2C9, activity is an important source of variability (Kaminsky LS and Zhang ZY, 1997) . Additionally, Rieder et al. (2005) have reported that an effect of the vitamin K epooxide reductase complex subunit 1 gene (VKORC1) has an important role on dose requirement. However, Takahashi et al. (2006) shows that Caucasians and African-Americans have high frequencies of VKORC1 and CYP2C9 genotypes, which lead to either reduced metabolic activity or attenuated sensitivity to warfarin, whereas only about 20% of the Japanese population possesses these genotypes. Therefore, further study of sources of variability in warfarin dose requirements among Japanese patients is warranted.