CYP3A4*22 and CYP3A5*3 impact efficacy and safety of diazepam in patients with alcohol withdrawal syndrome

Abstract

Background

Diazepam is one of the most commonly prescribed pharmaceuticals for the treatment of alcohol withdrawal syndrome (AWS). However, diazepam sometimes is ineffective, and some patients experience dose-dependent adverse drug reactions (ADR). Previous studies have shown that diazepam metabolism involves the CYP3A4 and CYP3A5 isoenzymes, whose activity is highly variable between individuals, which may contribute to differences in clinical response.

Purpose

The study aimed to investigate the effects of the genetic polymorphisms CYP3A4*22 and CYP3A5*3 on the efficacy and safety of diazepam in patients with AWS.

Materials and methods

One hundred male AWS patients received 30 mg/day diazepam by intramuscular injections for 5 days. Genotyping for CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) was performed by real-time polymerase chain reaction with allele-specific hybridization. The efficacy and safety assessments were performed using psychometric scales.

Results

Patients who carry CT and TT genotypes by polymorphic marker C > T intron 6 (rs35599367) of the CYP3A4 gene had a higher risk for ADR and demonstrated lower safety of diazepam therapy (p < 0.001; two-way ANOVA).

Conclusion

These results suggest that genotyping for common CYP3A variants might have the potential to guide benzodiazepine withdrawal treatment.

Keywords:

• Pharmacogenetics
• personalized medicine
• diazepam
• benzodiazepines
• alcohol withdrawal

Acknowledgement

The research received no external funding.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Notes on contributors

Valentin Yurievich Skryabin, PhD, is a chair of a department at the addiction clinic and an associate professor. His primary research fields are pharmacogenetics and personalized medicine, psychiatry and mental health, addictology, and clinical pharmacology.

Johan Franck is the Professor of Psychiatry (full professor) at Karolinska Institutet. His research focuses mainly on the effects of pharmaceutical drugs on drug-craving, drug-seeking behavior and relapse to illicit drug use in patients with addictive disorders.

Volker Martin Lauschke is associate professor and group leader in personalized medicine and drug development at Karolinska Institutet. His research group integrates 3D cell culture systems of primary human cells, microfluidics and comprehensive molecular profiling technologies to discover novel therapeutic strategies.

Mikhail Sergeevich Zastrozhin, PhD, is a head of laboratory of genetics and fundamental studies. His primary study fields are pharmacogenetics, pharmacogenomics, pharmacotranscriptomics and others ‘-omics’ biomarkers. The secondary interests are data mining, statistical analysis, R, psychiatry, and clinical pharmacology.

Valery Valerievich Shipitsyn is a vice-director of Moscow Research and Practical Centre on Addictions. His primary study field is addictology.

Evgeny Alekseevich Bryun, Professor, is the chief substance abuse specialist of the Ministry of health of the Russian Federation. He is a President of the Moscow Research and Practical Centre on Addictions. The primary research interests are psychiatry and addictology.

Dmitry Alekseevich Sychev is the Corresponding member of the Academy of Sciences of Russia, Professor and head of clinical pharmacology and therapy department. His primary study fields are pharmacogenetics and personalized medicine.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.