Pharmacogenomics of anticoagulants: steps toward personal dosage

Coumarin anticoagulants, including warfarin, are among the most widely prescribed drugs in modern medicine. A difficulty with their use is that dosage needs to be individually determined for each patient, usually by following a standard initial dosing protocol, measuring the coagulation rate regularly (using the international normalized ratio, INR, which is a measure of prothrombin time. A high INR value indicates overcoagulation) and then adjusting the dose until the required rate of coagulation is obtained. Overcoagulation places the patient at risk of potentially fatal hemorrhage, so improving protocols for initiation of anticoagulant treatment remains an important issue. In particular, warfarin has been shown to be frequently implicated in emergency admissions relating to adverse drug reactions in a survey of two UK hospitals [1]. Approximately 10% of Europeans require an unusually low dose of warfarin (1.5 mg/day or less) and these patients could be at increased risk of developing serious bleeds and undesirably high levels of anticoagulation, especially during the initial weeks of treatment [2]. Although the current oral coumarin anticoagulants, such as warfarin, acenocoumarol and phenprocoumon, are likely to be replaced eventually by other drugs under development, such as the specific thrombin inhibitors, the current drugs will probably continue to be the main oral anticoagulants prescribed in the short to medium term.The metabolism of warfarin and the other coumarin anticoagulants is well understood, with the cytochrome P450 enzyme CYP2C9 having a major role in their phase I metabolism (reviewed in [3]). CYP2C9 is subject to a genetic polymorphism affecting its activity, and the fact that this polymorphism contributes to individual anticoagulant dose requirement is now well established, although its effect on phenprocoumon metabolism is less pronounced than that on either warfarin or acenocoumarol [2,4-7]. Coumarin anticoagulants exert their effect by inhibit