Pharmacogenetics of oral anticoagulants: the opportunity for individualized drug treatment of greater safety.

Abstract

Oral antivitamin K (AVK) anticoagulants are widely prescribed for the prophylaxis and treatment of a number of thromboembolic disorders. They constitute a major cause of iatrogenic accidents because of their narrow therapeutic index and consequently increase both thrombotic and bleeding risk; thus, regular monitoring is required. Patient and environmental factors affect the anticoagulation response and it has become evident that the wide interindividual variation in AVK response is also partly genetically determined. The main enzyme responsible for the metabolism of AVKs is hepatic cytochrome P450 CYP2C9. Vitamin K epoxide reductase complex subunit I (VKORC1) is a key enzyme in the vitamin K cycle; it is required to regenerate the cofactor essential for the activation of vitamin K-dependent clotting factors and is the target enzyme of AVK inhibition. Genetic variations affecting both CYP2C9 and VKORC1 are associated with variability in drug response and may explain differences in dose requirements. Genotyping for CYP2C9 and VKORC1 variants before initiation of treatment could allow clinicians to develop dosing protocols and identify patients at higher risk for AVK complications such as bleeding.