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; alcohol withdrawal; benzodiazepines; diazepam; personalized medicine.