ORIGINAL PAPER Acenocoumarol sensitivity and pharmacokinetic characterization of CYP2C9 *5/*8,*8/*11,*9/*11 and VKORC1*2 in black African healthy Beninese subjects Aurel Constant Allabi • Yves Horsmans • Jean-Claude Alvarez • Andre ´ Bigot • Roger K. Verbeeck • Umit Yasar • Jean-Luc Gala Received: 30 May 2011 / Accepted: 14 July 2011 / Published online: 3 August 2011 Ó Springer-Verlag France 2011 Abstract This study aimed at investigating the contri- bution of CYP2C9 and VKORC1 genetic polymorphisms to inter-individual variability of acenocoumarol pharmacoki- netics 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 adminis- tration 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 pharmaco- dynamic response to acenocoumarol is highly variable between the subjects. This variability seems to be associ- ated with CYP2C9*5/*8 and *9/*11 variant and demo- graphic 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. Keywords CYP2C9 Á VKORC1 Á Acenocoumarol Á INR Á Benin Á African 1 Introduction Vitamin K antagonists (VKAs), such as warfarin, aceno- coumarol and phenprocoumon, are life-saving drugs, but A. C. Allabi (&) Unite ´ de Pharmacologie, Faculte ´ des Sciences de la Sante ´ de Cotonou, Universite ´ d’Abomey-Calavi, Campus du Champ de Foire, 01 BP 188 Cotonou, Benin e-mail: acallabi@hotmail.com Y. Horsmans Clinical Pharmacology Unit, UCL, Brussels, Belgium J.-C. Alvarez Laboratory of Pharmacology-Toxicology, Garches Hospital, AP-HP, Universite ´ Versailles Saint-Quentin, 92380 Garches, France A. Bigot Unite ´ d’Immunologie, Faculte ´ des Sciences de la Sante ´ de Cotonou, UAC, Cotonou, Benin R. K. Verbeeck Ecole de Pharmacie, UCL, Brussels, Belgium R. K. Verbeeck Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa U. Yasar Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey J.-L. Gala Laboratory of Applied Molecular Technology, UCL, Brussels, Belgium 123 Eur J Drug Metab Pharmacokinet (2012) 37:125–132 DOI 10.1007/s13318-011-0056-7