Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to fluindione

Br J Clin Pharmacol. 2012 Mar;73(3):428-36. doi: 10.1111/j.1365-2125.2011.04095.x.


Aim: Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to fluindione.

Methods: Four hundred sixty-five patients with a venous thromboembolic event treated by fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, fluindione doses and bleeding events were collected.

Results: VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001) and on the time to obtain a first INR value > 4 (P= 0.0002). The average daily dose of fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7mg (±6.2) for VKORC1 CT and 8.2mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to fluindione.

Conclusions: VKORC1 genotype strongly affected anticoagulation induced by fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anticoagulants / pharmacology*
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Blood Coagulation / drug effects*
  • Blood Coagulation / genetics
  • Case-Control Studies
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P450 Family 4
  • Dose-Response Relationship, Drug
  • Epoxide Hydrolases / genetics*
  • Female
  • Genotype
  • Humans
  • International Normalized Ratio
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / genetics*
  • Pharmacogenetics
  • Phenindione / analogs & derivatives*
  • Phenindione / pharmacology
  • Polymorphism, Genetic / drug effects
  • Time Factors
  • Vitamin K Epoxide Reductases


  • Anticoagulants
  • Phenindione
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P450 Family 4
  • CYP4F2 protein, human
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases
  • Epoxide Hydrolases
  • EPHX1 protein, human
  • fluindione