Неврология, нейропсихиатрия, психосоматика (Apr 2020)

Pharmacogenetics of the safety of phenazepam in alcohol withdrawal syndrome: haplotype and combinatorial analyses of polymorphic variants in the pharmacokinetic factor genes

  • D. V. Ivashchenko,
  • O. V. Tereshchenko,
  • I. I. Temirbulatov,
  • K. A. Akmalova,
  • E. A. Grishina,
  • M. S. Zastrozhin,
  • L. M. Savchenko,
  • E. A. Bryun,
  • D. A. Sychev

DOI
https://doi.org/10.14412/2074-2711-2020-2-17-22
Journal volume & issue
Vol. 12, no. 2
pp. 17 – 22

Abstract

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Phenazepam is a benzodiazepine tranquilizer that is widely used in Russia. The drug is metabolized by cytochrome P450 3A (CYP3A) isozymes. Since their substrates have an affinity for P-glycoprotein, the polymorphic variants in the ABCB1 gene may affect the safety of this drug.Objective: to analyze associations between the CYP3A5, CYP2C9, CYP2C19, CYP2D6 and ABCB1 gene polymorphisms and the safety of phenazepam treatment for alcohol withdrawal syndrome (AWS).Patients and methods. The investigation enrolled 102 patients diagnosed with uncomplicated AWS (IDC-10 code F10.30). All the patients were followed up for 6 days within which they took phenazepam. 5-ml venous blood samples were collected from each patient for genotyping. The carriage of CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*17, CYP2C9*2, ABCB1 3435C>T, 1236C>T, and 2677G>T/A polymorphic variants was determined by a real-time polymerase chain reaction assay. Therapy safety was evaluated using the UKU Side-Effect Rating Scale on day 6. Statistical analysis was carried out with SPSS Statistics 21.0. Haplotype and combinatorial analyses were performed using SNPStats.Results and discussion. The greater subjective severity of adverse reactions (ARs) was shown for the homozygotes of ABCB1 1236C>T CC (odds ratio (OR), 2.154; 95% confidence interval (CI), 1.271–3.650; p=0.014) and ABCB1 2677G>T GG (OR, 2.154; 95% CI, 1.271–3.650; p=0.014). On the contrary, a combinatorial analysis revealed the role of ABCB1 3435C>T, 1236C>T, and 2677G>T polymorphic alleles as predictors for the greater subjective severity of ARs. The following statistically significant polymorphic variant combinations were ABCB1 3435-1236–2677 and T-T-T-CYP3A5*3 isozymes (OR=5.03; 95% CI, 1.65–15.34; p=0.0056); T-T-T-CYP2C9*1 (OR=3.61; 95% CI, 1.31–9.92; p=0.015); T-T-T-CYP2C19*1 (OR=2.52; 95% CI, 1.05–6.08; p=0.042). Attention disorders were also established to be associated with the carriage of T-T-T-CYP2D6*1 (OR=2.58; 95 CI, 1.08–6.13; p=0.035).Conclusion. The carriage of ABCB1 3435-2677-1236 (T-T-T) haplotype is significantly associated with the greater severity of ARs in phenazepam-treated patients with AWS.

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