title: Influence of CYP2C9 and VKORC1 polymorphisms on warfarin and acenocoumarol in a sample of Lebanese people.
abstract: The authors assessed the impact of CYP2C9*2, CYP2C9*3, and/or VKORC1-1639G>A/1173C>T single-nucleotide polymorphisms on oral anticoagulants in a Lebanese population. This study recruited 231 Lebanese participants on long-term warfarin or acenocoumarol maintenance therapy with an international normalized ratio (INR) monitored at the American University of Beirut Medical Center. CYP2C9 and VKORC1 variant alleles were screened by real-time PCR. Plasma R- and S-warfarin and R- and S-acenocoumarol levels were assayed using high-performance liquid chromatography. The variant allele frequencies of CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A/1173C>T were 15.4%, 7.8%, and 52.4%, respectively. Fifty-five participants were excluded from analysis because of nontherapeutic INR values at recruitment, leaving 43 participants taking warfarin and 133 taking acenocoumarol. There was a significant decrease in the weekly maintenance dose of both drugs with CYP2C9 and VKORC1 variants when compared with wild-type patients. CYP2C9*2 had the least impact on the response to both drugs. The concentrations of R- and S-warfarin in plasma were significantly correlated with CYP2C9 genotypes. For acenocoumarol, time to reach target INR was more prolonged in patients carrying any CYP2C9 variant allele but failed to reach statistical significance because of low numbers of patients. There was no association between allelic variants and bleeding events. This is the first pharmacogenetic study of oral anticoagulants in Arabs. The authors showed that both CYP2C9 and VKORC1 polymorphisms are common in Lebanon and influence warfarin and acenocoumarol dose requirements, with the CYP2C9*2 polymorphism having less effect on acenocoumarol, the most commonly used oral anticoagulant in Lebanon.
authors.affiliation: Pharmacology & Therapeutics, Faculty of Medicine, American University of Beirut, Riad El Solh, Beirut 1107 2020, Lebanon.
authors.forename: Maria O
authors.initials: MO
authors.lastname: Esmerian
authors.forename: Zahi
authors.initials: Z
authors.lastname: Mitri
authors.forename: Mohammad-Zuheir
authors.initials: MZ
authors.lastname: Habbal
authors.forename: Eddy
authors.initials: E
authors.lastname: Geryess
authors.forename: Ghazi
authors.initials: G
authors.lastname: Zaatari
authors.forename: Samir
authors.initials: S
authors.lastname: Alam
authors.forename: Hadi N
authors.initials: HN
authors.lastname: Skouri
authors.forename: Rami A
authors.initials: RA
authors.lastname: Mahfouz
authors.forename: Ali
authors.initials: A
authors.lastname: Taher
authors.forename: Nathalie K
authors.initials: NK
authors.lastname: Zgheib
mesh_terms: D000074:Acenocoumarol / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D007861:Lebanon / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D013927:Thrombosis / Q000453:epidemiology / Q000517:prevention & control; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; 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