title: Acenocoumarol sensitivity and pharmacokinetic characterization of CYP2C9 *5/*8,*8/*11,*9/*11 and VKORC1*2 in black African healthy Beninese subjects.
abstract: 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.
authors.affiliation: Unité de Pharmacologie, Faculté des Sciences de la Santé de Cotonou, Université d'Abomey-Calavi, Campus du Champ de Foire, 01 BP 188, Cotonou, Benin. acallabi@hotmail.com
authors.forename: Aurel Constant
authors.initials: AC
authors.lastname: Allabi
authors.forename: Yves
authors.initials: Y
authors.lastname: Horsmans
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Alvarez
authors.forename: André
authors.initials: A
authors.lastname: Bigot
authors.forename: Roger K
authors.initials: RK
authors.lastname: Verbeeck
authors.forename: Umit
authors.initials: U
authors.lastname: Yasar
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Gala
mesh_terms: D000074:Acenocoumarol / Q000493:pharmacokinetics* / Q000494:pharmacology; D000328:Adult; D000367:Age Factors; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001541:Benin; D044383:Black People; D015992:Body Mass Index; D002853:Chromatography, Liquid / Q000379:methods; 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*; D011110:Polymorphism, Genetic; D053719:Tandem Mass Spectrometry / Q000379:methods; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; 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; D000074:Acenocoumarol