Email this article 
IMPACT OF CYP3A5, CYP2C9, CYP2C19, AND CYP2D6 POLYMORPHISMS ON PHENAZEPAM SAFETY IN PATIENTS WITH ALCOHOL WITHDRAWAL SYNDROME
- Authors: Ivashchenko D.V.1, Ryzhikova K.A.1, Sozaeva Z.A.1, Pimenova Y.A.1, Grishina E.A.1, Zastrozhin M.S.1,2, Aguzarov A.D.2, Savchenko L.M.1, Bryun E.A.1,2, Sychev D.A.1
-
Affiliations:
- Russian Medical Academy of Continuous Professional Education
- Moscow Research Practical Center of Narcology
- Issue: Vol 73, No 3 (2018)
- Pages: 206-214
- Section: PSYCHOLOGY AND PSYCHIATRY: CURRENT ISSUES
- URL: https://vestnikramn.spr-journal.ru/jour/article/view/989
- DOI: https://doi.org/10.15690/vramn989
- ID: 989
Cite item
Full Text
Abstract
Introduction: Phenazepam is the Russian original benzodiazepine tranquilizer. We conducted first pharmacogenetic study on Phenazepam’s safety in patients with alcohol withdrawal syndrome. Isoenzymes CYP3A4, CYP3A5, CYP2C9, and CYP2C19 are involved into benzodiazepine tranquilizers’ metabolism.
Aim: To determine predictive value of CYP3A5, CYP2C9, CYP2C19, and CYP2D6 genetic polymorphisms and their haplotypes for adverse reaction risk associated with the treatment with phenazepam.
Materials and methods: The study enrolled 102 male patients with non-comlicated alcohol withdrawal syndrome (F10.3 by ICD-10) who entered the study group in 24 hours after the admission to hospital and was administered Phenazepam for 6 days. Therapy safety was evaluated with UKU Side Effects Rating Scale on the 6th day of treatment. 5 ml of venous blood was collected from each participant for genotyping to detect CYP3A5*3, CYP2С9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2C19*17, and CYP2D6*4 polymorphisms by real-time polymerase chain reaction. Haplotype analysis was performed by SNPStats online-tool. Statistical analysis was made in SPSS Statistics 21.0.
Results: In overall sample (n=102) CYP2C9*3 increased risk of «Increased duration of sleep» (OR 1.46; 95% CI 1.11−1.9; p=0.037) and «Constipation» (OR 13.1; 95% CI 1.44−119.2; p=0.02). The following results in subgroup «Phenazepam’s monotherapy» (n=64) were observed: CYP3A5*3 increased global severity of adverse drug reactions according to patient’s opinion (OR 2.79; 95% CI 1.26−6.22; p=0.031); CYP2C9*3 led to «Increased duration of sleep» (OR 1.57; 95% CI 1.14−2.17; p=0.034). Haplotype CYP3A5*3-CYP2C19*2-CYP2C19*17 (G-G-T) was associated with increased risk of «Concentration difficulties (OR 2.86; 95% CI 0.96−8.50; p=0.061).
Conclusion: The study findings confirmed that CYP2C9*3, CYP3A5*3, and CYP2C19*2 polymorphisms can decrease the phenazepam safety rate in patients with alcohol withdrawal syndrome. The result of haplotype analysis revealed that only CYP3A5*3-CYP2C19*2-CYP2C19*17 (G-G-T) can be used as a significant predictor of adverse reaction to phenazepam.
About the authors
D. V. Ivashchenko
Russian Medical Academy of Continuous Professional Education
Author for correspondence.
Email: dvi1991@yandex.ru
ORCID iD: 0000-0002-2295-7167
Dmitriy V. Ivashchenko – MD.
Moscow
Russian FederationK. A. Ryzhikova
Russian Medical Academy of Continuous Professional Education
Email: kriistinkaa@mail.ru
ORCID iD: 0000-0003-3505-8520
KristinaA. Ryzhikova.
Moscow
Russian FederationZh. A. Sozaeva
Russian Medical Academy of Continuous Professional Education
Email: zhannet.sozaeva@gmail.com
ORCID iD: 0000-0001-5166-7903
ZhannetA. Sozaeva.
Moscow
Russian FederationY. A. Pimenova
Russian Medical Academy of Continuous Professional Education
Email: yulia.pimenova@bk.ru
ORCID iD: 0000-0002-9031-2272
Yulija V. Pimenova.
Moscow
Russian FederationE. A. Grishina
Russian Medical Academy of Continuous Professional Education
Email: gelana2010@yandex.ru
ORCID iD: 0000-0002-5621-8266
Elena A. Grishina - PhD, Assistant professor.
Moscow
Russian FederationM. S. Zastrozhin
Russian Medical Academy of Continuous Professional Education; Moscow Research Practical Center of Narcology
Email: rudnmed@yandex.ru
ORCID iD: 0000-0003-0607-4812
Mikhail S. Zastrozhin - MD, PhD.
Moscow
Russian FederationA. D. Aguzarov
Moscow Research Practical Center of Narcology
Email: aguzarov.ad@yandex.ru
ORCID iD: 0000-0001-7664-998X
Albert D. Aguzarov – MD.
Moscow
Russian FederationL. M. Savchenko
Russian Medical Academy of Continuous Professional Education
Email: uch_sovet@rmanpo.ru
ORCID iD: 0000-0002-2411-3494
Lyudmila M. Savchenko - MD, PhD, Professor.
Moscow
Russian FederationE. A. Bryun
Russian Medical Academy of Continuous Professional Education; Moscow Research Practical Center of Narcology
Email: ea.bryun@yandex.ru
ORCID iD: 0000-0002-8366-9732
Eugeniy A. Bryun - MD, PhD, Professor.
Moscow
Russian FederationD. A. Sychev
Russian Medical Academy of Continuous Professional Education
Email: dmytry.alex.sychev@gmail.com
ORCID iD: 0000-0002-4496-3680
Dmitriy A. Sychev - MD, PhD, Professor.
Moscow
Russian FederationReferences
- Воронина Т.А., Середенин С.Б. Перспективы поиска новых анксиолитиков // Экспериментальная и клиническая фармакология. ― 2002. ― Т.65. ― №5 ― С. 4–17.
- Головенко Н.Я., Зинковский В.Г., Богатский А.В., и др. Сравнительное изучение экскреции метаболитов феназепама при однократном и множественном введении белым крысам // Химико-фармацевтический журнал. ― 1979. ― Т.13. ― №1 ― С. 21–26.
- Середенин С.Б., Воронина Т.А., Незнамов Г.Г., Жердев В.П. Феназепам. 25 лет в медицинской практике. ― М.: Наука; 2007. ― 384 c.
- Осадший Ю.Ю., Вобленко Р.А., Арчаков Д.С., Тараканова Е.А. Место бензодиазепинов в современной терапии психических расстройств (обзор доказательных исследований) // Современная терапия психических расстройств. ― 2016. ― №1 ― С. 2–10.
- Ладыженский М.Я., Городничев А.В., Костюкова Е.Г. Бензодиазепиновые анксиолитики: востребованы ли они сегодня? // Современная терапия психических расстройств. ― 2014. ― №2 ― С. 20–25.
- Fukasawa T, Suzuki A, Otani K. Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines. J Clin Pharm Ther. 2007;4(32):333–341. doi: 10.1111/j.13652710.2007.00829.x.
- Ham AC, Ziere G, Broer L, et al. CYP2C9 genotypes modify benzodiazepine-related fall risk: original results from three studies with meta-analysis. J Am Med Dir Assoc. 2016;1(18):88.e1–88.e15. doi: 10.1016/j.jamda.2016.09.021.
- Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;4(92):414–417. doi: 10.1038/clpt.2012.96.
- de Jonge H, Elens L, de Loor H, et al. The CYP3A4*22 C>T single nucleotide polymorphism is associated with reduced midazolam and tacrolimus clearance in stable renal allograft recipients. Pharmacogenomics J. 2015;15(2):144–152. doi: 10.1038/tpj.2014.49.
- Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;4(27):383–391. doi: 10.1038/86882.
- Werk AN, Cascorbi I. Functional gene variants of CYP3A4. Clin Pharmacol Ther. 2014;96(3):340–348. doi: 10.1038/clpt.2014.129.
- Hiratsuka M. Genetic polymorphisms and in vitro functional characterization of CYP2C8, CYP2C9, and CYP2C19 allelic variants. Biol Pharm Bull. 2016;39(11):1748–1759. doi: 10.1248/ bpb.b16-00605.
- Fricke-Galindo I, Céspedes-Garro C, Rodrigues-Soares F, et al. Interethnic variation of CYP2C19 alleles, ‘predicted’ phenotypes and ‘measured’ metabolic phenotypes across world populations. Pharmacogenomics J. 2016;16(2):113–123. doi: 10.1038/ tpj.2015.70.
- Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103–141. doi: 10.1016/j.pharmthera.2012.
- Lerena LА, Naranjo ME, Rodrigues-Soares F, et al. Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. Expert Opin Drug Metab Toxicol. 2014;10(11):1569–1583. doi: 10.1517/17425255.2014.964204.
- Jose M, Mathaiyan J, Kattimani S, et al. Role of CYP2C19 gene polymorphism in acute alcohol withdrawal treatment with loading dose of diazepam in a South Indian population. Eur J Clin Pharmacol. 2016;72(7):807–812. doi: 10.1007/s00228-0162061-x.
- Иващенко Д.В., Рыжикова К.А., Созаева Ж.А., и др. Влияние генетических полиморфизмов CYP2C9*2 и CYP2C9*3 на профиль безопасности бензодиазепиновых транквилизаторов у больных с синдромом отмены алкоголя // Наркология. ― 2017. ― Т.16. ― №4 ― С. 52–66.
- Иващенко Д.В., Рыжикова К.А., Созаева Ж.А., и др. Изучение ассоциации полиморфизма гена CYP3A5 rs776746 с безопасностью феназепама у пациентов с синдромом отмены алкоголя // Наркология. ― 2017. ― Т.16. ― №3 ― С. 36–47.
- Иващенко Д.В., Рыжикова К.А., Созаева Ж.А., и др. Полиморфизм CYP2D6*4 (rs3892097) слабо ассоциирован с безопасностью бромдигидрохлорфенилбензодиазепина у пациентов с СОА: результаты фармакогенетического исследования // Наркология. ― 2017. ― Т.16. ― №8 ― С. 43–51
- Иващенко Д.В., Рыжикова К.А., Созаева Ж.А., и др. Фармакогенетическая оценка риска развития нежелательных побочных реакций при приеме бромдигидрохлорфенилбензодиазепина пациентами с синдромом отмены алкоголя: роль полиморфизмов гена CYP2C19 // World Journal of Personalized Medicine. ― 2017. ― Т.1. ― №1 ― С. 18–26. doi: 10.14341/wjpm9262.
- Practice guideline for the pharmacological treatment of patients with alcohol use disorder. American Psychiatric Association; 2018. 226 p.
- Lingjaerde O, Ahlfors UG, Bech P, et al. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptictreated patients. Acta Psychiatr Scand Suppl. 1987;334:1–100.
Supplementary files
