The effect of CYP2C9, VKORC1 genotypes and old age on warfarin pharmacologic sensitivity in korean patients with thromboembolic disease

Ann Clin Lab Sci. 2011 Summer;41(3):229-35.

Abstract

The therapeutic dose of warfarin is dependent upon intrinsic patient characteristics that are highly variable. We assessed the effects of CYP2C9, VKORC1 1173 C/T polymorphisms, and old age on warfarin dosing and sensitivity by measuring plasma S-/R-warfarin levels in Korean patients. INR and the plasma S-/R-warfarin concentrations were determined in 58 patients who had the VKORC1 1173C/T CYP2C9 genotypes, were on a long-term anticoagulation regimen with warfarin, and took a daily dose of warfarin. The pharmacokinetic sensitivity of warfarin was significantly higher in the CYP2C9 *1/*3 genotypes than in the CYP2C9 *1/*1 genotypes [ratio of S-warfarin concentration/dose, 0.53 vs. 0.21; p=0.01]. Pharmacodynamic sensitivity in older patients (≥ 75 years) with the CYP2C9 *1/*1 and VKORC1 1173 TT genotypes was significantly higher as compared to younger patients (<75 years) [Ratio of INR/S-warfarin concentration, 4.88 vs. 3.41; p = 0.026]. The CYP2C9*3 allele and old age (≥ 75 years) with the VKORC1 1173 T allele were also associated with increased risk of over-anticoagulation. The increase of over-anticoagulation risk and warfarin sensitivity is related to the CYP2C9*3 allele and old age with the VKORC1 1173 T allele in Korean patients with thromboembolic disease. These findings suggest that a lower initial and maintenance dose should be considered for the patients with CYP2C9 *3 allele and advanced age in this patient population. However, due to the limited number of patients in the study population, our finding needs to be confirmed by a larger, well-controlled study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / drug effects*
  • Aging / ethnology
  • Aging / metabolism
  • Anticoagulants / therapeutic use*
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Asian People / genetics
  • Blood Coagulation / drug effects
  • Blood Coagulation / genetics
  • Cytochrome P-450 CYP2C9
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Korea / epidemiology
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / genetics*
  • Thromboembolism* / drug therapy
  • Thromboembolism* / ethnology
  • Thromboembolism* / genetics
  • Thromboembolism* / metabolism
  • Treatment Outcome
  • Vitamin K Epoxide Reductases
  • Warfarin / pharmacokinetics
  • Warfarin / therapeutic use*

Substances

  • Anticoagulants
  • Warfarin
  • Mixed Function Oxygenases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases