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Acenocoumarol sensitivity and pharmacokinetic characterization of CYP2C9 *5/*8,*8/*11,*9/*11 and VKORC1*2 in black African healthy Beninese subjects

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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.

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Acknowledgments

The authors would like to thank the staff of the Hospital (Hôpital de Zone de COVE) for their technical assistance. We also wish to thank Angelbert Agbokponto for his help in the clinical part of the study; Veronique Schlumder for her technical assistance for genotyping; and Dr Paul Aliu to review internally this article.

Conflict of interest

The authors have no conflict of interest regarding this work.

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Authors and Affiliations

  1. 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

    Aurel Constant Allabi

  2. Clinical Pharmacology Unit, UCL, Brussels, Belgium

    Yves Horsmans

  3. Laboratory of Pharmacology-Toxicology, Garches Hospital, AP-HP, Université Versailles Saint-Quentin, 92380, Garches, France

    Jean-Claude Alvarez

  4. Unité d’Immunologie, Faculté des Sciences de la Santé de Cotonou, UAC, Cotonou, Benin

    André Bigot

  5. Ecole de Pharmacie, UCL, Brussels, Belgium

    Roger K. Verbeeck

  6. Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa

    Roger K. Verbeeck

  7. Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Umit Yasar

  8. Laboratory of Applied Molecular Technology, UCL, Brussels, Belgium

    Jean-Luc Gala

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  1. Aurel Constant Allabi
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  2. Yves Horsmans
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  3. Jean-Claude Alvarez
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  6. Umit Yasar
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  7. Jean-Luc Gala
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Correspondence to Aurel Constant Allabi.

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Allabi, A.C., Horsmans, Y., Alvarez, JC. et al. Acenocoumarol sensitivity and pharmacokinetic characterization of CYP2C9 *5/*8,*8/*11,*9/*11 and VKORC1*2 in black African healthy Beninese subjects. Eur J Drug Metab Pharmacokinet 37, 125–132 (2012). https://doi.org/10.1007/s13318-011-0056-7

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