Acenocoumarol sensitivity and pharmacokinetic characterization of CYP2C9 *5/*8 , *8/*11 , *9/*11 and VKORC1*2 in black African healthy Beninese subjects
European journal of drug metabolism and pharmacokinetics(2011)
摘要
This study aimed at investigating the contribution of CYP2C9 and VKORC1 genetic polymorphisms to inter-individual variability of acenocoumarol pharmacokinetics and pharmacodynamics in Black Africans from Benin. Fifty-one healthy volunteers were genotyped for VKORC1 1173C>T polymorphism. All of the subjects had previously been genotyped for CYP2C9*5 , CYP2C9*6 , CYP2C9*8 , CYP2C9*9 and CYP2C9*11 alleles. Thirty-six subjects were phenotyped with a single 8 mg oral dose of acenocoumarol by measuring plasma concentrations of ( R )- and ( S )-acenocoumarol 8 and 24 h after the administration using chiral liquid-chromatography tandem mass-spectrometry. International normalized ratio (INR) values were determined prior to and 24 h after the drug intake. The allele frequency of VKORC1 variant (1173C>T) was 1.96% (95% CI 0.0–4.65%). The INR values did not show statistically significant difference between the CYP2C9 genotypes, but were correlated with body mass index and age at 24 h post-dosing ( P < 0.05). At 8 h post dose, the ( S )-acenocoumarol concentrations in the CYP2C9*5/*8 and CYP2C9*9/*11 genotypes were about 1.9 and 5.1 fold higher compared with the CYP2C9*1/*1 genotype and 2.2- and 6.0-fold higher compared with the CYP2C9*1/*9 group, respectively. The results indicated that pharmacodynamic response to acenocoumarol is highly variable between the subjects. This variability seems to be associated with CYP2C9*5/*8 and *9/*11 variant and demographic factors (age and weight) in Beninese subjects. Significant association between plasma ( S )-acenocoumarol concentration and CYP2C9 genotypes suggested the use of ( S )-acenocoumarol for the phenotyping purpose. Larger number of subjects is needed to study the effect of VKORC1 1173C>T variant due to its low frequency in Beninese population.
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关键词
CYP2C9, VKORC1, Acenocoumarol, INR, Benin, African
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