{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T14:23:21Z","timestamp":1793283801816,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Diazepam is a benzodiazepine widely prescribed for the management of patients with severe alcohol withdrawal syndrome to prevent agitation, withdrawal seizures, and delirium tremens. Despite standard dosing of diazepam, a subset of patients experience refractory withdrawal syndromes or adverse drug reactions, such as impaired motor coordination, dizziness, and slurred speech. The CYP2C19 and CYP3A4 enzymes play a key role in the biotransformation of diazepam. Given the highly polymorphic nature of the CYP2C19 gene, we reviewed the clinical impact of variants in the CYP2C19 gene on both the pharmacokinetics of diazepam and treatment outcomes related to the management of alcohol withdrawal syndrome.<\/jats:p>","DOI":"10.3390\/jpm13020285","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T02:05:28Z","timestamp":1675389928000},"page":"285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Clinical Impact of the CYP2C19 Gene on Diazepam for the Management of Alcohol Withdrawal Syndrome"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2489-3099","authenticated-orcid":false,"given":"Teresa T.","family":"Ho","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Noble","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bao Anh","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katlynd","family":"Sunjic","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheeba Varghese","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of South Florida College of Pharmacy, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7978-9280","authenticated-orcid":false,"given":"Jacques","family":"Turgeon","sequence":"additional","affiliation":[{"name":"Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0686-4462","authenticated-orcid":false,"given":"Rustin D.","family":"Crutchley","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy, Washington State University, College of Pharmacy and Pharmaceutical Sciences, Yakima, WA 98901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"ref_1","unstructured":"(2023, January 20). Key Substance Use and Mental Health Indicators in the United States: Results from the 2020 National Survey on Drug Use and Health, Available online: https:\/\/www.samhsa.gov\/data\/sites\/default\/files\/reports\/rpt35325\/NSDUHFFRPDFWHTMLFiles2020\/2020NSDUHFFR1PDFW102121.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association. [5th ed.].","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/S0140-6736(09)60009-X","article-title":"Alcohol-use disorders","volume":"373","author":"Schuckit","year":"2009","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/phar.1770","article-title":"Management of Acute Alcohol Withdrawal Syndrome in Critically Ill Patients","volume":"36","author":"Dixit","year":"2016","journal-title":"Pharmacotherapy"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"ASAM Quality Improvement Council (2020). The ASAM Clinical Practice Guideline on Alcohol Withdrawal Management. J. Addict. Med., 14, e280.","DOI":"10.1097\/ADM.0000000000000731"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s40263-016-0403-y","article-title":"Diazepam in the Treatment of Moderate to Severe Alcohol Withdrawal","volume":"31","author":"Weintraub","year":"2017","journal-title":"CNS Drugs"},{"key":"ref_7","first-page":"VE01","article-title":"Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond","volume":"9","author":"Sachdeva","year":"2015","journal-title":"J. Clin. Diagn Res."},{"key":"ref_8","unstructured":"(2023, January 29). Valium Food and Drug Administration (FDA) Labeling, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2016\/013263s094lbl.pdf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s40263-014-0163-5","article-title":"Inpatient management of acute alcohol withdrawal syndrome","volume":"28","author":"Perry","year":"2014","journal-title":"CNS Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S494","DOI":"10.1097\/CCM.0b013e3181ec5412","article-title":"Alcohol withdrawal syndromes in the intensive care unit","volume":"38","author":"Sarff","year":"2010","journal-title":"Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1097\/01.CCM.0000256841.28351.80","article-title":"A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens","volume":"35","author":"Gold","year":"2007","journal-title":"Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/BF03161171","article-title":"Resistant alcohol withdrawal: Does an unexpectedly large sedative requirement identify these patients early?","volume":"2","author":"Hack","year":"2006","journal-title":"J. Med. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"270","DOI":"10.4103\/0976-500X.99440","article-title":"Determinants of success of loading dose diazepam for alcohol withdrawal: A chart review","volume":"3","author":"Bharadwaj","year":"2012","journal-title":"J. Pharmacol. Pharmacother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/j.1365-2710.2007.00829.x","article-title":"Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines","volume":"32","author":"Fukasawa","year":"2007","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1124\/jpet.104.067660","article-title":"UDP-glucuronosyltransferase (UGT) 2B15 pharmacogenetics: UGT2B15 D85Y genotype and gender are major determinants of oxazepam glucuronidation by human liver","volume":"310","author":"Court","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"01079","DOI":"10.3389\/fphar.2020.01079","article-title":"Inhibitory Effect of Imperatorin on the Pharmacokinetics of Diazepam In Vitro and In Vivo","volume":"11","author":"Zhou","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1002\/cpt.1973","article-title":"PharmVar GeneFocus: CYP2C19","volume":"109","author":"Botton","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_18","unstructured":"PharmGKB (2023, January 20). Gene-Specific Information Tables for CYP2C19. Available online: https:\/\/www.pharmgkb.org\/page\/cyp2c19RefMaterials."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/gim.2016.87","article-title":"Standardizing terms for clinical pharmacogenetic test results: Consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC)","volume":"19","author":"Caudle","year":"2017","journal-title":"Genet. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jmoldx.2018.01.011","article-title":"Recommendations for Clinical CYP2C19 Genotyping Allele Selection: A Report of the Association for Molecular Pathology","volume":"20","author":"Pratt","year":"2018","journal-title":"J. Mol. Diagn."},{"key":"ref_21","first-page":"369","article-title":"Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes","volume":"13","author":"Martis","year":"2013","journal-title":"Pharm. J."},{"key":"ref_22","unstructured":"(2023, January 29). Pharmacogene Variation Consortium. Available online: https:\/\/www.pharmvar.org\/gene\/CYP3A4."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.2217\/pgs.11.90","article-title":"Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors\u2019 dose requirements and trough blood levels in stable renal transplant patients","volume":"12","author":"Elens","year":"2011","journal-title":"Pharmacogenomics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1002\/cpt.690","article-title":"Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects","volume":"102","author":"Zhou","year":"2017","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s40265-015-0358-1","article-title":"Identification and management of alcohol withdrawal syndrome","volume":"75","author":"Mirijello","year":"2015","journal-title":"Drugs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/j.1365-2125.1996.tb00010.x","article-title":"The elimination of diazepam in Chinese subjects is dependent on the mephenytoin oxidation phenotype","volume":"42","author":"Wan","year":"1996","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1053\/cp.1999.v66.103379001","article-title":"Effect of the gene dosage of CgammaP2C19 on diazepam metabolism in Chinese subjects","volume":"66","author":"Qin","year":"1999","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.clpt.2005.08.020","article-title":"CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia","volume":"78","author":"Inomata","year":"2005","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/clpt.1989.40","article-title":"Importance of genetic factors in the regulation of diazepam metabolism: Relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype","volume":"45","author":"Bertilsson","year":"1989","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1177\/0018578720931756","article-title":"Effects of CYP2C19*17 Genetic Polymorphisms on the Steady-State Concentration of Diazepam in Patients With Alcohol Withdrawal Syndrome","volume":"56","author":"Skryabin","year":"2021","journal-title":"Hosp. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1097\/YPG.0000000000000306","article-title":"Effects of CYP2C19*17 genetic polymorphisms on plasma and saliva concentrations of diazepam in patients with alcohol withdrawal syndrome","volume":"32","author":"Skryabin","year":"2022","journal-title":"Psychiatr. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1097\/JCP.0000000000000340","article-title":"Extreme Duration of Diazepam-Associated Sedation in a Patient With Alcohol Delirium and CYP2C19 Polymorphisms","volume":"35","author":"Garmen","year":"2015","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/clpt.1990.12","article-title":"Effect of omeprazole treatment on diazepam plasma levels in slow versus normal rapid metabolizers of omeprazole","volume":"47","author":"Andersson","year":"1990","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0009-9236(95)90193-0","article-title":"Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4\u2019-hydroxylation","volume":"58","author":"Ishizaki","year":"1995","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/clpt.1992.125","article-title":"Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin","volume":"52","author":"Sohn","year":"1992","journal-title":"Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5197","DOI":"10.3748\/wjg.14.5197","article-title":"Maintenance time of sedative effects after an intravenous infusion of diazepam: A guide for endoscopy using diazepam","volume":"14","author":"Sugimoto","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Skryabin, V.Y., Zastrozhin, M.S., Torrado, M.V., Grishina, E.A., Ryzhikova, K.A., Shipitsyn, V.V., Galaktionova, T.E., Sorokin, A.S., Bryun, E.A., and Sychev, D.A. (2020). How do CYP2C19*2 and CYP2C19*17 genetic polymorphisms affect the efficacy and safety of diazepam in patients with alcohol withdrawal syndrome?. Drug Metab. Pers. Ther., 35.","DOI":"10.1515\/dmpt-2019-0026"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1007\/s00228-016-2061-x","article-title":"Role of CYP2C19 gene polymorphism in acute alcohol withdrawal treatment with loading dose of diazepam in a South Indian population","volume":"72","author":"Jose","year":"2016","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_39","unstructured":"(2023, January 29). Diastat Food and Drug Administration (FDA) Labeling, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2016\/020648s014lbl.pdf."},{"key":"ref_40","unstructured":"(2022, December 19). Assignment of CPIC Levels for Genes\/Drugs. Available online: https:\/\/cpicpgx.org\/prioritization\/#cpicLevels."},{"key":"ref_41","unstructured":"(2023, January 29). PharmGKB Clinical Annotations. Available online: https:\/\/www.pharmgkb.org\/chemical\/PA449283\/clinicalAnnotation."},{"key":"ref_42","first-page":"691","article-title":"Appraisal and development of evidence-based clinical decision support to enable perioperative pharmacogenomic application","volume":"21","author":"Borden","year":"2021","journal-title":"Pharm. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/08039488.2022.2065531","article-title":"CYP3A4*22 and CYP3A5*3 impact efficacy and safety of diazepam in patients with alcohol withdrawal syndrome","volume":"77","author":"Skryabin","year":"2022","journal-title":"Nord. J. Psychiatry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1177\/0897190021997000","article-title":"Using the CYP3A Activity Evaluation to Predict the Efficacy and Safety of Diazepam in Patients With Alcohol Withdrawal Syndrome","volume":"35","author":"Skryabin","year":"2022","journal-title":"J. Pharm. Pract."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/2\/285\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:22:57Z","timestamp":1760120577000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/2\/285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,3]]},"references-count":44,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["jpm13020285"],"URL":"https:\/\/doi.org\/10.3390\/jpm13020285","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,3]]}}}