World Journal of Personalized Medicine

Advanced search

Pharmacogenetic evaluation of adverse events’ risk in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine: The role of CYP2C19 gene polymorphisms


Introduction. Bromdihydrochlorphenylbenzodiazepine is the Russian original tranquilizer which widely using in psychiatry, narcology, neurology and general medicine. Particularly, that drug prescribing for patients with alcohol withdrawal syndrome (AWS). Isoenzyme CYP2C19 takes part in metabolism of the most of benzodiazepines, so the gene CYP2C19 might be included into pharmacogenetics study of bromdihydrochlorphenylbenzodiazepine. There was no study of CYP2C19 polymorphisms as biomarkers of bromdihydrochlorphenylbenzodiazepine’s safety.

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. 38 participants were added Pagluferal (contains phenobarbitalum, natrium coffeine-benzoate, bromisoval, papaverine) and/or Carbamazepine. Blood samples were analyzed to detect the CYP2C19*2 (rs4244285), *3 (rs4986893) и *17 (rs12248560) polymorphisms. Safety of therapy was evaluated with UKU Side Effects Rating Scale. Data analysis was performed with SPSS Statistics 21.0.

Results. Carriers of CYP2C19*2 GA+AA genotypes compared to GG homozygous significantly more often had such adverse effects as «Polyuria/polydipsia» in mean grade of penetration (33,3% vs 9%, p=0,016) and “Palpitations/Tachycardia” (16,7% vs 3,8%, p=0,018). Observed relationship between «Polyuria/polydipsia» and CYP2C19*2 GA+AA genotypes was confirmed in the subgroup “Combined pharmacotherapy” (37,5% vs 0%, p=0,006). CYP2C19*17 polymorphism in tendency to significance was associated with less frequent AE «Polyuria/polydipsia» among patients taking bromdihydrochlorphenylbenzodiazepine as monotherapy carriers of allele T had that AE in 16,9%, and CC homozygous in 24,2% (p=0,067).

Conclusion. Significant associations between CYP2C19*2 polymorphism and several AE in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine. Substantial role of CYP2C19*17 as predictor of AE associated with bromdihydrochlorphenylbenzodiazepine was not confirmed. Gene CYP2C19 is the sufficient biomarker of bromdihydrochlorphenylbenzodiazepine’s safety profile and needs further research.

About the Authors

Dmitriy V. Ivashchenko

Russian Medical Academy of Continuous Professional Education

Russian Federation


Kristina A. Ryzhykova

Russian Medical Academy of Continuous Professional Education

Russian Federation

Zhannet A. Sozaeva

Russian Medical Academy of Continuous Professional Education

Russian Federation

Mikhail S. Zastrozhin

Russian Medical Academy of Continuous Professional Education;  Moscow Research Practical Center of Narcology

Russian Federation


Elena A. Grishina

Russian Medical Academy of Continuous Professional Education

Russian Federation

Lyudmila M. Savchenko

Russian Medical Academy of Continuous Professional Education

Russian Federation


Eugeniy A. Bryun

Russian Medical Academy of Continuous Professional Education; Moscow Research Practical Center of Narcology

Russian Federation

MD, PhD, Professor

Dmitriy A. Sychev

Russian Medical Academy of Continuous Professional Education

Russian Federation

MD, PhD, Professor


1. Ладыженский М.Я., Городничев А.В., Костюкова Е.Г. Бензодиазепиновые анксиолитики: востребованы ли они сегодня? // Современная терапия психических расстройств. 2014; 2: 20-25 [Ladyjensky MY, Gorodnichev AV, Kostyukova EG. Benzodiazepine anxiolytics: demand are they today? Sovremennayaterapiyapsikhicheskikhrasstroystv. 2014;(2):20-25. (in Russ.)]

2. Осадший Ю.Ю., Вобленко Р.А., Арчаков Д.С. и др. Место бензодиазепинов в современной терапии психических расстройств (обзор доказательных исследований). // Современная терапия психических расстройств. – 2016. – №1. – С. 2-10. [Osadshiy Y, Voblenko R, Archakov D, Tarakanova E. Benzodiazepines. An attempt to arrive at an informed consensus. Sovremennaya terapiya psikhicheskikh rasstroystv. 2016;(1): 2-10. (in Russ.)]

3. Sachdeva A, Choudhary M, Chandra M. Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond. J Clin Diagn Res. 2015;9(9):VE01-VE07. doi: 10.7860/JCDR/2015/13407.6538

4. Longo LP, Johnson B. Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives. Am Fam Physician. 2000;61(7):2121-2128.

5. De Witte P, Pinto E, Ansseau M, Verbanck P. Alcohol and withdrawal: from animal research to clinical issues. Neurosci Biobehav Rev. 2003;27(3):189-197.

6. Saari TI, Uusi-Oukari M, Ahonen J, Olkkola KT. Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology. Pharmacol Rev. 2011;63(1):243-267. doi: 10.1124/pr.110.002717

7. Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev. 2008;60(3):243-260. doi: 10.1124/pr.108.00505

8. Алкогольный абстинентный синдром. Под ред. Афанасьева В.В. – СПб, «Интермедика», 2002. - 336 с. [Afanasyev VV, editor. Alkogol’nyy abstinentnyy sindrom. Saint Petersburg: Intermedika; 2002. 336 p. (in Russ.)]

9. Kurko TA, Saastamoinen LK, Tahkapaa S, et al. Long-term use of benzodiazepines: Definitions, prevalence and usage patterns - a systematic review of register-based studies. Eur Psychiatry. 2015;30(8):1037-1047. doi: 10.1016/j.eurpsy.2015.09.003

10. Lu XM, Zhu JP, Zhou XM. The effect of benzodiazepines on insomnia in patients with chronic obstructive pulmonary disease: a meta-analysis of treatment efficacy and safety. Int J Chron Obstruct Pulmon Dis. 2016;11:675-685. doi: 10.2147/COPD.S98082

11. chaefer TJ, Hafner JW. Are benzodiazepines effective for alcohol withdrawal? Ann Emerg Med. 2013;62(1):34-35. doi: 10.1016/j.annemergmed.2012.03.017

12. Liang J, Olsen RW. Alcohol use disorders and current pharmacological therapies: the role of GABA(A) receptors. Acta Pharmacol Sin. 2014;35(8):981-993. doi: 10.1038/aps.2014.50

13. Wong A, Benedict NJ, Lohr BR, et al. Management of benzodiazepine-resistant alcohol withdrawal across a healthcare system: Benzodiazepine dose-escalation with or without propofol. Drug Alcohol Depend. 2015;154:296-299. doi: 10.1016/j.drugalcdep.2015.07.005

14. Bonnet U, Lensing M, Specka M, Scherbaum N. Comparison of two oral symptom-triggered pharmacological inpatient treatments of acute alcohol withdrawal: clomethiazole vs. clonazepam. Alcohol Alcohol. 2011;46(1):68-73. doi: 10.1093/alcalc/agq081

15. Rubio G, Lopez-Munoz F, Ponce G, et al. Zonisamide versus diazepam in the treatment of alcohol withdrawal syndrome. Pharmacopsychiatry. 2010;43(7):257-262. doi: 10.1055/s-0030-1263168

16. Addolorato G, Leggio L, Abenavoli L, et al. Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study vs diazepam. Am J Med. 2006;119(3):276 e213-278. doi: 10.1016/j.amjmed.2005.08.042

17. Crispo AL, Daley MJ, Pepin JL, et al. Comparison of clinical outcomes in nonintubated patients with severe alcohol withdrawal syndrome treated with continuous-infusion sedatives: dexmedetomidine versus benzodiazepines. Pharmacotherapy. 2014;34(9):910-917. doi: 10.1002/phar.1448

18. Sen S, Grgurich P, Tulolo A, et al. A Symptom-Triggered Benzodiazepine Protocol Utilizing SAS and CIWA-Ar Scoring for the Treatment of Alcohol Withdrawal Syndrome in the Critically Ill. Ann Pharmacother. 2017;51(2):101-110. doi: 10.1177/1060028016672036

19. Fukasawa T, Suzuki A, Otani K. Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines. J Clin Pharm Ther. 2007;32(4):333-341. doi: 10.1111/j.1365-2710.2007.00829.x

20. Kawakami H, Ohtsuki S, Kamiie J, et al. Simultaneous absolute quantification of 11 cytochrome P450 isoforms in human liver microsomes by liquid chromatography tandem mass spectrometry with in silico target peptide selection. J Pharm Sci. 2011;100(1):341-352. doi: 10.1002/jps.22255

21. 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

22. De Morais SM, Wilkinson GR, Blaisdell J, et al. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol. 1994;46(4):594-598.

23. Rudberg I, Mohebi B, Hermann M, et al. Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther. 2008;83(2):322-327. doi: 10.1038/sj.clpt.6100291

24. Fricke-Galindo I, Cespedes-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

25. 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/s00228-016-2061-x

26. Parmeggiani A, Posar A, Sangiorgi S, Giovanardi-Rossi P. Unusual side-effects due to clobazam: a case report with genetic study of CYP2C19. Brain Dev. 2004;26(1):63-66.

27. Saruwatari J, Ogusu N, Shimomasuda M, et al. Effects of CYP2C19 and P450 oxidoreductase polymorphisms on the population pharmacokinetics of clobazam and N-desmethylclobazam in japanese patients with epilepsy. Ther Drug Monit. 2014;36(3):302-309. doi: 10.1097/FTD.0000000000000015

28. Kosaki K, Tamura K, Sato R, et al. A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam. Brain Dev. 2004;26(8):530-534. doi: 10.1016/j.braindev.2004.02.010

29. Inomata S, Nagashima A, Itagaki F, et al. CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia. Clin Pharmacol Ther. 2005;78(6):647-655. doi: 10.1016/j.clpt.2005.08.020

30. Fukasawa T, Yasui-Furukori N, Suzuki A, et al. Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity. Eur J Clin Pharmacol. 2005;61(11):791-795. doi: 10.1007/s00228-005-0032-8

31. Suzuki Y, Shioiri T, Muratake T, et al. Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles. Eur J Clin Pharmacol. 2003;58(12):829-833. doi: 10.1007/s00228-003-0563-9

32. Qin XP, Xie HG, Wang W, et al. Effect of the gene dosage of CgammaP2C19 on diazepam metabolism in Chinese subjects. Clin Pharmacol Ther. 1999;66(6):642-646. doi: 10.1016/S0009-9236(99)90075-9

33. Порсева Н.Ю., Дворская О.Н., Солонинина А.В. Регламентация обращения лекарственных препаратов, производных бензодиазепина // Современные проблемы науки и образования. – 2013. – №3. – C. 357. [Porseva NY, Dvorskaya ON, Soloninina AV. Regulation of circulation of medicines, benzodiazepine derivatives. Sovremennye problemy nauki i obrazovaniya. 2013;(3):357. (in Russ.)]

34. Maskell PD, De Paoli G, Nitin Seetohul L, Pounder DJ. Phenazepam: the drug that came in from the cold. J Forensic Leg Med. 2012;19(3):122-125. doi: 10.1016/j.jflm.2011.12.014

35. Drummer OH, Odell M. The forensic pharmacology of drugs of abuse. UK, London: Arnold London; 2001.

36. 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 neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1-100.

37. Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169(4):505-514. doi: 10.1093/aje/kwn359

Supplementary files

1. Таблица номер 2 к статье CYP2C19 Иващенко ДВ
Type Исследовательские инструменты
Download (16KB)    
Indexing metadata


For citation:

Ivashchenko D.V., Ryzhykova K.A., Sozaeva Z.A., Zastrozhin M.S., Grishina E.A., Savchenko L.M., Bryun E.A., Sychev D.A. Pharmacogenetic evaluation of adverse events’ risk in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine: The role of CYP2C19 gene polymorphisms. World Journal of Personalized Medicine. 2017;1(1):18-26. (In Russ.)

Views: 2711

ISSN 2587-733X (Online)