IMPACT OF CYP3A5, CYP2C9, CYP2C19, AND CYP2D6 POLYMORPHISMS ON PHENAZEPAM SAFETY IN PATIENTS WITH ALCOHOL WITHDRAWAL SYNDROME

Cover Page
  • 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:
    1. Russian Medical Academy of Continuous Professional Education
    2. 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
  • Cite item

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.


D. V. Ivashchenko

Russian Medical Academy of Continuous Professional Education

Author for correspondence.
Email: dvi1991@yandex.ru
ORCID iD: 0000-0002-2295-7167

Russian Federation

Dmitriy V. Ivashchenko – MD.

Moscow

K. A. Ryzhikova

Russian Medical Academy of Continuous Professional Education

Email: kriistinkaa@mail.ru
ORCID iD: 0000-0003-3505-8520

Russian Federation

KristinaA. Ryzhikova.

Moscow

Zh. A. Sozaeva

Russian Medical Academy of Continuous Professional Education

Email: zhannet.sozaeva@gmail.com
ORCID iD: 0000-0001-5166-7903

Russian Federation

ZhannetA. Sozaeva.

Moscow

Y. A. Pimenova

Russian Medical Academy of Continuous Professional Education

Email: yulia.pimenova@bk.ru
ORCID iD: 0000-0002-9031-2272

Russian Federation

Yulija V. Pimenova.

Moscow

E. A. Grishina

Russian Medical Academy of Continuous Professional Education

Email: gelana2010@yandex.ru
ORCID iD: 0000-0002-5621-8266

Russian Federation

Elena A. Grishina - PhD, Assistant professor.

Moscow

M. 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

Russian Federation

Mikhail S. Zastrozhin - MD, PhD.

Moscow

A. D. Aguzarov

Moscow Research Practical Center of Narcology

Email: aguzarov.ad@yandex.ru
ORCID iD: 0000-0001-7664-998X

Russian Federation

Albert D. Aguzarov – MD.

Moscow

L. M. Savchenko

Russian Medical Academy of Continuous Professional Education

Email: uch_sovet@rmanpo.ru
ORCID iD: 0000-0002-2411-3494

Russian Federation

Lyudmila M. Savchenko - MD, PhD, Professor.

Moscow

E. 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

Russian Federation

Eugeniy A. Bryun - MD, PhD, Professor.

Moscow

D. A. Sychev

Russian Medical Academy of Continuous Professional Education

Email: dmytry.alex.sychev@gmail.com
ORCID iD: 0000-0002-4496-3680

Russian Federation

Dmitriy A. Sychev - MD, PhD, Professor.

Moscow

  1. Воронина Т.А., Середенин С.Б. Перспективы поиска новых анксиолитиков // Экспериментальная и клиническая фармакология. ― 2002. ― Т.65. ― №5 ― С. 4–17.
  2. 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.
  3. Середенин С.Б., Воронина Т.А., Незнамов Г.Г., Жердев В.П. Феназепам. 25 лет в медицинской практике. ― М.: Наука; 2007. ― 384 c.
  4. 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.
  5. Ладыженский М.Я., Городничев А.В., Костюкова Е.Г. Бензодиазепиновые анксиолитики: востребованы ли они сегодня? // Современная терапия психических расстройств. ― 2014. ― №2 ― С. 20–25.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. Werk AN, Cascorbi I. Functional gene variants of CYP3A4. Clin Pharmacol Ther. 2014;96(3):340–348. doi: 10.1038/clpt.2014.129.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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
  20. 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.
  21. Practice guideline for the pharmacological treatment of patients with alcohol use disorder. American Psychiatric Association; 2018. 226 p.
  22. 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.

Views

Abstract - 26

PDF (Russian) - 9

Cited-By


PlumX



Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies