Warfarin, the coumarin derivatives, is the most widely prescribed anticoagulant for thromboembolic disorders. This test detects variants within two genes, CYP2C9 and VKORC1, that impact the rate of warfarin metabolism. Understanding different rates of warfarin metabolism can help define optimal, patient-specific warfarin dosage.
The metabolism of drugs is also influenced by ethnicity, diet, and other medications. All factors should be considered prior to initiating new therapy.
VKORC1 (vitamin K epoxide reductase complex subunit 1) and cytochrome P450 CYP2C9 account for up to 50% of the interindividual variability of the warfarin response. These genetic markers may serve as clinically relevant predictors of warfarin dosing.
The presence of the heterozygous promoter variant (-1639 G>A) in the VKORC1 gene can result in warfarin resistance. The homozygous or compound heterozygous missense mutations in the VKORC1 gene leads to combined deficiency of vitamin K dependent coagulation factor type 2 (VKCFD2). The risk of complication during oral anticoagulation is high. Low dosage warfarin treatment should be considered.
The presence of the *2 and/or *3 alleles in the CYP2C9 gene can result in poor metabolizer (PM) phenotypes. The PM phenotype is associated with lack of enzyme activity, and the drug may be metabolized slowly or not at all. This results in increased concentrations of the drug with a reduced or absent therapeutic response and the potential for serious side effects. Warfarin metabolism is reduced by 30% to 50% by *2 allele and 90% by *3 allele. This effect may be more pronounced in Asians as compared to Caucasians. Individuals with at least one copy of *2 or *3 have an increased risk of bleeding compared to individuals without *2 or *3. A lower maintenance dose may be required. Coadministration of inhibitors of CYP2C9, such as phenylbutazone, sulfinpyrazone, amiodarone, miconazole, isoniazid, ticlopidine, tamoxifen, and fluconazole, will increase the anticoagulation effect. The azole antifungal agent fluconazole (DiflucanŽ) is a potent inhibitor of CYP2C9. Fluconazole, at conventional doses, abolishes CYP2C9 activity. Rifampin, barbiturates, carbamazepine, and St John's wort will increase warfarin metabolism and increase the chance of reduced efficacy, and the warfarin dose may need to be increased.