Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter March 5, 2020

How do CYP2C19*2 and CYP2C19*17 genetic polymorphisms affect the efficacy and safety of diazepam in patients with alcohol withdrawal syndrome?

  • Valentin Yu Skryabin ORCID logo EMAIL logo , Mikhail S. Zastrozhin , Marco V. Torrado , Elena A. Grishina , Kristina A. Ryzhikova , Valery V. Shipitsyn , Tatiana E. Galaktionova , Alexander S. Sorokin , Evgeny A. Bryun and Dmitry A. Sychev



Diazepam is one of the most commonly prescribed tranquilizers for therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on its efficacy and safety. The objective of our study was to investigate the effect of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy and safety of diazepam in patients with AWS.


The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions.


Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 681G>A (CYP2C19*2, rs4244285) genotypes: (CYP2C19*1/*1) −8.5 [−15.0; −5.0], (CYP2C19*1/*2 and CYP2C19*2/*2) −12.0 [−13.0; −9.0], p = 0.021. The UKU scale scores, which were used to evaluate the safety of therapy, were also different: (CYP2C19*1/*1) 7.0 [6.0; 12.0], (CYP2C19*1/*2 and CYP2C19*2/*2) 9.5 [8.0; 11.0], p = 0.009. Patients carrying different CYP2C19 –806C>T (CYP2C19*17, rs12248560) genotypes also demonstrated differences in therapy efficacy and safety rates.


Thus, the effects of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy of diazepam were demonstrated.

  1. Author contributions: All the authors accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


[1] Lee JA, Duby JJ, Cocanour CS. Effect of early and focused benzodiazepine therapy on length of stay in severe alcohol withdrawal syndrome. Clin Toxicol (Phila). 2019;57:624–27.10.1080/15563650.2018.1542701Search in Google Scholar PubMed

[2] Trevisan LA, Boutros N, Petrakis IL, Krystal JH. Complications of alcohol withdrawal: pathophysiological insights. Alcohol Health Res World. 1998;22:61–6.Search in Google Scholar

[3] Sachdeva A, Choudhary M, Chandra M. Alcohol withdrawal syndrome: benzodiazepines and beyond. J Clin Diagn Res. 2015;9:VE01–7.10.7860/JCDR/2015/13407.6538Search in Google Scholar PubMed PubMed Central

[4] Benedict NJ, Wong A, Cassidy E, Lohr BR, Pizon AF, Smithburger PL, et al. Predictors of resistant alcohol withdrawal (RAW): a retrospective case-control study. Drug Alcohol Depend. 2018;192:303–8.10.1016/j.drugalcdep.2018.08.017Search in Google Scholar PubMed

[5] Sarff M, Gold JA. Alcohol withdrawal syndromes in the intensive care unit. Crit Care Med. 2010;38(9 Suppl):494–501.10.1097/CCM.0b013e3181ec5412Search in Google Scholar PubMed

[6] Gold JA, Rimal B, Nolan A, Nelson LS. A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Crit Care Med. 2007;35:724–30.10.1097/01.CCM.0000256841.28351.80Search in Google Scholar PubMed PubMed Central

[7] Bird RD, Makela EH. Alcohol withdrawal: what is the benzodiazepine of choice? Ann Pharmacother. 1994;28:67–71.10.1177/106002809402800114Search in Google Scholar PubMed

[8] Weintraub SJ. Diazepam in the treatment of moderate to severe alcohol withdrawal. CNS Drugs. 2017;31:87–95.10.1007/s40263-016-0403-ySearch in Google Scholar PubMed

[9] Calcaterra NE, Barrow JC. Classics in chemical neuroscience: diazepam (valium). ACS Chem Neurosci. 2014;5:253–60.10.1021/cn5000056Search in Google Scholar PubMed PubMed Central

[10] Fukasawa T, Suzuki A, Otani K. Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines. J Clin Pharm Ther. 2007;32:333–41.10.1111/j.1365-2710.2007.00829.xSearch in Google Scholar PubMed

[11] Andersson T, Miners JO, Veronese ME, Birkett DJ. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin Pharmacol. 1994;38:131–7.10.1111/j.1365-2125.1994.tb04336.xSearch in Google Scholar PubMed PubMed Central

[12] Jung F, Richardson TH, Raucy JL, Johnson EF. Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases. Drug Metab Dispos. 1997;25:133–9.Search in Google Scholar

[13] Oneda B, Crettol S, Jaquenoud Sirot E, Bochud M, Ansermot N, et al. The P450 oxidoreductase genotype is associated with CYP3A activity in vivo as measured by the midazolam phenotyping test. Pharmacogenet Genomics. 2009;19:877–83.10.1097/FPC.0b013e32833225e7Search in Google Scholar

[14] Fukasawa T, Yasui-Furukori N, Suzuki A, Inoue Y, Tateishi T, Otani K. Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity. Eur J Clin Pharmacol. 2005;61:791–5.10.1007/s00228-005-0032-8Search in Google Scholar

[15] Lepper ER, Baker SD, Permenter M, Ries N, van Schaik RH, Schenk PW, et al. Effect of common CYP3A4 and CYP3A5 variants on the pharmacokinetics of the cytochrome P450 3A phenotyping probe midazolam in cancer patients. Clin Cancer Res. 2005;11:7398–404.10.1158/1078-0432.CCR-05-0520Search in Google Scholar

[16] Yang TJ, Shou M, Korzekwa KR, Gonzalez FJ, Gelboin HV, Yang SK. Role of cDNA-expressed human cytochromes P450 in the metabolism of diazepam. Biochem Pharmacol. 1998;55:889–96.10.1016/S0006-2952(97)00558-3Search in Google Scholar

[17] Jose M, Mathaiyan J, Kattimani S, Adithan S, Chandrasekaran A. 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;72:807–12.10.1007/s00228-016-2061-xSearch in Google Scholar PubMed

[18] Nuss MA, Elnicki DM, Dunsworth TS, Makela EH. Utilizing CIWA-Ar to assess use of benzodiazepines in patients vulnerable to alcohol withdrawal syndrome. W V Med J. 2004;100:21–5.Search in Google Scholar

[19] Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. 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;334:1–100.10.1111/j.1600-0447.1987.tb10566.xSearch in Google Scholar PubMed

[20] Garmén AK, Pettersson N, Unge C, Lindh JD. Extreme duration of diazepam-associated sedation in a patient with alcohol delirium and CYP2C19 polymorphisms. J Clin Psychopharmacol. 2015;35:475–7.10.1097/JCP.0000000000000340Search in Google Scholar PubMed

[21] Wan J, Xia H, He N, Lu YQ, Zhou HH. The elimination of diazepam in Chinese subjects is dependent on the mephenytoin oxidation phenotype. Br J Clin Pharmacol. 1996;42:471–4.10.1111/j.1365-2125.1996.tb00010.xSearch in Google Scholar

[22] Zastrozhin MS, Grishina EA, Ryzhikova KA, Smirnov VV, Savchenko LM, Bryun EA, et al. The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction. Pharmacogenomics Pers Med. 2018;11:1–5.10.2147/PGPM.S144503Search in Google Scholar PubMed PubMed Central

[23] Zastrozhin MS, Bryun EA, Skryabin VY, Sychev DA, Grishina EA, Ryzhikova KA, et al. Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration. Drug Metab Pers Ther. 2017;32:129–36.Search in Google Scholar

[24] Zastrozhin MS, Savchenko LM, Bryun EA, Brodyansky VM, Kibitov AO, Skryabin VY, et al. Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder. Pharmacogenomics Pers Med. 2017;10:209–15.10.2147/PGPM.S140700Search in Google Scholar PubMed PubMed Central

Received: 2019-09-24
Accepted: 2020-01-17
Published Online: 2020-03-05

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 28.3.2023 from
Scroll Up Arrow