Genotypes Associated With Reduced Activity of VKORC1 and CYP2C9 and Their Modification of Acenocoumarol Anticoagulation During the Initial Treatment Period

Abstract

The objective of this study was to investigate the influence of genotypes associated with reduced activity of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) on anticoagulation with acenocoumarol during the first 6 weeks of treatment. In 1,525 patients from the Rotterdam Study who were started on anticoagulation therapy with acenocoumarol, the presence of VKORC1 1173C>T and CYP2C9*2 and *3 allele variants was determined. The first international normalized ratio (INR) after initial standard dose, risk of overanticoagulation, and mean dosage at the end of the initiation period were compared between genotypes. The initial standard dosage significantly increased the risk of severe overanticoagulation by 85% for each additional VKORC1 T-allele present. At the end of the initiation period, each VKORC1 T-allele present was shown to decrease the required acenocoumarol dosage by 5.1 mg/week, while each CYP2C9 variant allele present reduced the required dosage by 1.8 mg/week. Our conclusion was that an initial standard dosing regimen with acenocoumarol increases the risk of severe overanticoagulation in patients with variant alleles of the VKORC1 and CYP2C9 genes.

Frequencies of polymorphisms in CYP2C9 and VKORC1 genes influencing warfarin metabolism in Slovak population: implication for clinical practice

“…The frequencies of selected SNPs correlate with other European populations (7,22,33,35,36,38,42) and thus with Caucasians (17). This type of study was done for the fi rst time in Slovakia.…”

Current Status of Pharmacogenetics in Antithrombotic Drug Therapy

“…CYP4F2 was shown to catalyze vitamin K oxidation, while the presence of 433Met variation reduced its catalytic ability, potentially leading to accumulation of the VKORC1 substrate -vitamin K epoxide and larger warfarin doses required for inhibition of this pathway (McDonald et al, 2009). CYP4F2 Val433Met was also associated with acenocoumarol dose requirements with similar modest effect (1.2-1.3%) (Perez-Andreu et al, 2009;Teichert et al, 2009).…”

“…The investigators found that carriers of *2,*3 required more time to achieve stable dosing (hazard ratio HR=0. (Stehle et al, 2008;Teichert et al, 2009). Thus, significant contribution of common hypofunctional CYP2C9 variants to warfarin sensitivity has been well-established, although accurate estimates of their contribution varies between studies and is dependent on inclusion of other factors.…”

Pharmacology

“…Although the FDA updated the warfarin label already in 2008 (Teichert et al, 2009a;Food and Drug Administration [FDA], 2007), genotyping preceding the anticoagulation therapy with coumarin derivatives is not commonly performed. Currently, health care professionals' attitudes are reserved towards pharmacogenetic dosing.…”