VKORC1 genotypes are associated with response to warfarin but free warfarin concentration during initial anticoagulation in healthy Chinese volunteers.
BACKGROUND
The genetic variations in VKORC1 modulate the stable responses to warfarin administration. But the role of VKORC1 polymorphisms during the initial anticoagulation and elimination period in the Han Chinese population is not clear.


METHODS
Twenty-four healthy Chinese volunteers were grouped according to their VKORC1 genotype. Twelve subjects were in the 3 mg group and 12 in the 6 mg group. VKORC1 genotypes were determined by a polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) assay and sequencing. The international normalized ratio (INR) was measured with an ACL9000 coagulation analyser. Plasma free warfarin concentration was measured with LC/MS/MS.


RESULTS
In the initial anticoagulation period, the -1639AG and 1173TC carriers compared with the -1639AA and 1173TT carriers had a low INR value. The differences between genotypes with regard to INR values were more obvious in the 3 mg subjects (P < 0.05), and were not significantly different among the 6 mg subjects (P > 0.05). On the contrary, no significant difference of plasma free warfarin concentration between genotypes was observed in each dosage group. It took 96 hours for the INR value and 144 hours for the free warfarin plasma concentration to come back to baselines after the last dose. No significant difference among genotypes and dosing groups was detected in the elimination phase (P > 0.05).


CONCLUSIONS
VKORC1 polymorphisms are associated with differences in the initial response to warfarin when given at fixed doses, without affecting, as expected, its plasma concentration.
Key Laboratory of Clinical Trial Research in Cardiovascular Drugs, Ministry of Health, Fu Wai Hospital.
Shuang
S
Xie
Hong
H
Liu
Lei
L
Tian
Juan-juan
JJ
Jiang
Guo-liang
GL
Chen
Li-wei
LW
Liu
Li
L
Xu
Yi-shi
YS
Li
D000328:Adult; D000925:Anticoagulants / Q000097:blood / Q000627:therapeutic use*; D044466:Asian People; D002853:Chromatography, Liquid; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics; D053719:Tandem Mass Spectrometry; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000097:blood / Q000627:therapeutic use*; D055815:Young Adult
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases