title: The effect of CYP2C9, VKORC1 genotypes and old age on warfarin pharmacologic sensitivity in korean patients with thromboembolic disease.
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.
authors.affiliation: Department of Laboratory Medicine, Konkuk University Hospital, 4-12, Hwayang-dong, Gwangjin-gu, Seoul, South Korea.
authors.forename: Hee-Won
authors.initials: HW
authors.lastname: Moon
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Noh
authors.forename: Yeo-Min
authors.initials: YM
authors.lastname: Yun
authors.forename: Hahn Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Ik Jin
authors.initials: IJ
authors.lastname: Yun
authors.forename: Junghan
authors.initials: J
authors.lastname: Song
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000187:drug effects* / Q000208:ethnology / Q000378:metabolism; D000925:Anticoagulants / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007723:Korea / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D013923:Thromboembolism / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases