VKORC1
Vitamin K epoxide reductase complex subunit 1 (EC 1.17.4.4) (Vitamin K1 2,3-epoxide reductase subunit 1) [VKOR] [MSTP134] [MSTP576] [UNQ308/PRO351]
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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.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Anticoagulants
- Aryl Hydrocarbon Hydroxylases
- Asian Continental Ancestry Group
- Blood Coagulation
- Cytochrome P-450 CYP2C9
- Dose-Response Relationship, Drug
- Female
- Humans
- Korea
- Male
- Middle Aged
- Mixed Function Oxygenases
- Thromboembolism
- Treatment Outcome
- Vitamin K Epoxide Reductases
- Warfarin
The objective of this study was to assess the contribution of the VKORC1 and CYP2C9 genotypes and age, body size, and weight of the patients to the warfarin dose requirement in a Chinese population. Blood samples were collected from 178 Chinese patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range (1.5-3.0). The polymorphisms for the VKORC1 (-1639GA) and CYP2C9*3 genotypes, venous INR, and plasma concentration and unbound concentration of warfarin were then analyzed. VKORC1 (-1639G>A) genotyping showed that 149 patients were homozygous AA, 28 were heterozygous GA, and one was homozygous for the GG genotype. CYP2C9*3 genotyping showed that 162 patients were *1/*1, and 16 patients were heterozygous *1/*3. Patients with the VKORC1(-1639 GG GA) (3.32 /- 1.02 mg/day) and CYP2C9*1/*1 (2.06 /- 0.82 mg/day) genotypes required a significantly higher warfarin dose than those with the -1639 AA (1.76 /- 0.57 mg/day; P < 0.001) or CYP2C9*1/*3 (1.60 /- 1.29 mg/day; P < 0.001), genotype. The multiple linear regression model for warfarin dose indicated significant contributions from age (r (2) = 0.084; P < 0.001), weight (r (2) = 0.063; P < 0.001), VKORC1 genotype (r (2) = 0.494; P < 0.001), and age, weight, and CYP2C9 and VKORC1 genotype together (r (2) = 0.628; P < 0.001). This study shows that age, weight and the VKORC1 and CYP2C9 polymorphism affect warfarin dose requirements in our sample of Chinese patients receiving long-term therapy and showing stable control of anticoagulation. It is anticipated that the use of dosing regimens modified by taking into account the contribution of age, weight, and the CYP2C9 and VKORC1 genotypes has the potential to improve the safety of warfarin therapy.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Anticoagulants
- Aryl Hydrocarbon Hydroxylases
- Blood Coagulation
- Body Weight
- China
- Cytochrome P-450 CYP2C9
- Female
- Genotype
- Humans
- International Normalized Ratio
- Male
- Middle Aged
- Mixed Function Oxygenases
- Pharmacogenetics
- Polymorphism, Genetic
- Vitamin K Epoxide Reductases
- Warfarin
The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory E(MAX) model, with S-warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S-warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Algorithms
- Anticoagulants
- Aryl Hydrocarbon Hydroxylases
- Cytochrome P-450 CYP2C9
- DNA
- Databases, Factual
- Female
- Genotype
- Humans
- Male
- Middle Aged
- Mixed Function Oxygenases
- Models, Statistical
- Pharmacokinetics
- Population
- Stereoisomerism
- Vitamin K Epoxide Reductases
- Warfarin