Pharmacogenetics of Warfarin

วารสารโลหติวทิยาและเวชศาสตร บรกิารโลหติ ป ที ่ 16 ฉบบัที ่ 3 กรกฎาคม-กนัยายน 2549 Warfarin is the mainstay of anticoagulation therapy. It is used for the prevention and treatment of venous thromboembolism, myocardial infarction, and strokes.1 Its clinical use, however, is complicated by the fact that it has a narrow therapeutic index with associated adverse effects that are potentially serious, i.e., bleeding, and the dosage requirement to produce a required degree of anticoagulation varies widely between patients. The reason for the latter is multifactorial and includes determinants such as drugs,1 age,2-4 diet,5 race and genetic factors.6-11 There has been, to date, no reliable means of predicting an individual's response to warfarin prior to initiating therapy. The discovery of common polymorphisms related to warfarin pharmacokinetics and pharmacodynamics over the last 10 years provides a unique opportunity to develop a pharmacogenetics-based approach to oral anticoagulant therapy. By using a pharmacogenetics-based approach to predict the patient's maintenance dose a priori, initiation of warfarin therapy may become safer and more efficient. Pharmacology of warfarin Warfarin produces its anticoagulant effect through the inhibition of vitamin K epoxide reductase (VKOR) (Figure 1). VKOR is a multicomponent lipid-protein enzyme system in the endoplasmic reticulum, which regenerates reduced vitamin K from its 2,3-epoxide.12 Reduced vitamin K or vitamin K hydroquinone is an essential cofactor for the post-translational γ-carboxylation of glutamic acid residues on coagulation factors II, VII, IX, and X, as well as the anticoagulant proteins C, S, and Z by γ-glutamyl carboxylase (GGC).1 Vitamin K epoxide reductase complex subunit 1 (VKORC1) is a recently identified gene that confers in vitro VKOR activity and is inhibited by warfarin.13,14 Warfarin depletes the pool of reduced vitamin K causing the liver to synthesize nonfunctional coagulation factors, and producing an anticoagulated state. Warfarin is manufactured as racemic mixtures of the Sand R-enantiomers, and after oral ingestion they are metabolized by the cytochrome P450 (CYP) complex (Figure 1). This cytochrome P450 is largely responsible for the metabolism Editorial Pharmacogenetics of Warfarin