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

• Published in: Clinical pharmacology and therapeutics Vol. 85; no. 4; pp. 379 - 386
• Main Authors: Teichert, M, Schaik, RHN, Hofman, A, Uitterlinden, AG, Smet, PAGM, Stricker, BHCh, Visser, LE
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-04-2009
• Subjects: Acenocoumarol - pharmacology; Acenocoumarol - therapeutic use; Aged; Aged, 80 and over; Alleles; Anticoagulants - pharmacology; Anticoagulants - therapeutic use; Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Biological and medical sciences; Cohort Studies; Cytochrome P-450 CYP2C9; Female; Genetic Variation - genetics; Genotype; Humans; Male; Medical sciences; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Pharmacology. Drug treatments; Polymorphism, Genetic - genetics; Prospective Studies; Vitamin K Epoxide Reductases; Human; Modification; Typing; Enzyme; Isozyme; Coumarine derivatives; Cytochrome P450; VKORC1 gene; Genotype; Anticoagulant; Biological activity; Antivitamin K; Treatment; Vitamin-K-epoxide reductase (warfarin-sensitive); Oxidoreductases; CYP2C9 gene; Acenocoumarol
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/clpt.2008.294

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.
Clinical Pharmacology & Therapeutics (2009); 85, 4, 379–386 doi:10.1038/clpt.2008.294