Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Miao
Liyan
L
Department of Clinical Pharmacology Research Lab, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China. miaolysuzhou@163.com
Yang
Jian
J
Huang
Chenrong
C
Shen
Zhenya
Z
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000925:Anticoagulants / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics*; D001835:Body Weight; D002681:China; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000494:pharmacology; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology
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