Abstract
A clinical effect of warfarin depends on highly polymorphic drug-metabolizing (CYP2C9) and drug-target (VKORC1) enzymes. The objective of this study was to investigate the impact of CYP2C9*2, CYP2C9*3, and VKORC1 (G-1639A) polymorphisms on the variability of warfarin dosage requirements in Lithuanian patients after heart valve replacement. The study included 83 patients with a mean age of 65.2 years (SD, 13.31) after heart valve replacement with an achieved stable international normalized ratio of 2-3.5. The restriction fragment length polymorphism method was used to identify polymorphisms of VKORC1 and CYP2C9. Daily warfarin dosage significantly correlated with weight (r=0.4087) and height (r=0.3883) of the patients. Patients younger than 60 years required significantly higher daily warfarin dosages than older patients. Two-thirds (66.3%) of the patients had the wild-type (WT) CYP2C9*1/*1 genotype; 38.6% and 54.2% of the patients had WT VKORC1 (G/G) and VKORC1 (G/A) genotypes, respectively. WT CYP2C9*1/*1 genotype was associated with a higher daily warfarin dosage (5.84 mg [SD, 2.84]) as compared to other CYP2C9 genotypes. Carriers of WT VKORC1 (G/G) required a higher warfarin dose as compared to (A/A) carriers (6.20±2.78 mg and 3.75±1.40 mg, respectively; P=0.04). Patients having CYP2C9*1/*1 or 1/*2 in combination with VKORC1 (G/G) or (G/A) genotypes required the highest daily warfarin dosage in comparison to other combinations of genotypes. The Lithuanian study sample is characterized by high a frequency (92.8%) of VKORC1 G/G and G/A genotypes that determines a higher warfarin-loading dose. Analysis of combined CYP2C9 and VKORC1 gene variants allows the prediction of warfarin dosage. These results can be used to individualize treatment with warfarin in the field of heart surgery in Lithuania.
Highlights
Warfarin is one of the most widely prescribed oral anticoagulants worldwide; it is used to prevent and treat venous or arterial thrombi and emboli associated with atrial fibrillation or cardiac valve replacement [1]
The Lithuanian study sample is characterized by high a frequency (92.8%) of VKORC1 G/G and G/A genotypes that determines a higher warfarin-loading dose
Analysis of combined cytochrome P450 2C9 (CYP2C9) and VKORC1 gene variants allows the prediction of warfarin dosage
Summary
Warfarin is one of the most widely prescribed oral anticoagulants worldwide; it is used to prevent and treat venous or arterial thrombi and emboli associated with atrial fibrillation or cardiac valve replacement [1]. S-warfarin is 3–5 times more active and metabolized primarily by cytochrome P450 2C9 (CYP2C9). S-warfarin has a higher clearance and a shorter half-life for elimination as compared with R-warfarin. These pharmacokinetic differences between the two enantiomers determine the higher circulating plasma levels of R-warfarin as compared with S-warfarin during prolonged treatment [3]. Both S- and R-warfarin block VKORC1 (vitamin K epoxide reductase), the main enzyme in the reduction pathway of vitamin K, which participates in the biotransformation of nonactive blood clotting factors into their active forms. In 2004, genetic variations within the gene encoding for a subunit of the vitamin K epoxide reductase complex, namely the VKORC1 gene, were found to correlate strongly with sensitivity to warfarin
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