Pharmacogenetics predictors of benzodiazepine tranquilizers'' adverse reactions
Introduction. Alcohol withdrawal syndrome (AWS) is the most frequent indication to prescribe benzodiazepine tranquilizers. According to plenty of studies, isoenzymes CYP3A4, CYP3A5 and CYP2C19 are main metabolizers of those drugs. Phenazepam is the most common benzodiazepine to treat AWS in Russia. There were no research of pharmacogenetics' predictors of Phenazepam's safety. Materials and methods. 102 male patients with non-comlicated AWS (F 10.3 by ICD-10) were involved into the study. During 6 days of dynamic observation each participant was prescribed bromdihydrochlorphenylbenzodiazepine (Phenazepam). 5 ml of venous blood was collected from each participant for genotyping. Blood samples were analyzed to detect CYP3A5*3 (6986A>G, rs776746), CYP2C19*2 (681G>A, rs4244285), CYP2C19*3 (363G>A, rs4986893), CYP2C19*17(-806C>T, rs12248560), CYP2C9*2 (rs1799853, 430C>T), CYP2C9*3 (1075A>C, rs1057910), CYP2D6*4 (1846G>A, rs3892097), ABCB1 3435C>T (rs1045642) polymorphisms. Safety of therapy was evaluated with UKU Side Effects Rating Scale. Data analysis was performed with SPSS Statistics 21.0. Results. Polymorphisms CYP3A5*3, CYP2C9*3, CYP2C19*2 and ABCB1 3435C>T were significantly associated with several adverse reactions according to UKU Scale. Carriers of those biomarkers more often had accomodation disturbances, polyuria/polydipsia, constipation, orthostatic dizzinness. There were no substantial associations of CYP2C19*17, CYP2C9*2, CYP2D6*4 with phenazepam-induced adverse reactions. Conclusion. Results determined leading role of CYP3A5*3, CYP2C9*3, ABCB1 3435C>T polymorphisms as biomarkers of phenazepam's safety in patients with alcohol withdrawal syndrome.