Relations of CYP2C19*2 genetic polymorphisms to plasma and saliva concentrations of diazepam in patients hospitalized for alcohol withdrawal

V Yu Skryabin,E A Bryun,M S Zastrozhin,K A Ryzhikova,T E Galaktionova,E A Grishina,D A Sychev,V V Shipitsyn

doi:10.52667/2712-9179-2021-1-1-84-92

Abstract

Diazepam is one of the most widely prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). However, diazepam therapy often turns out to be ineffective, and some patients experience dose-dependent adverse drug reactions. Previous studies have shown that the metabolism of diazepam involves the CYP2C19 isoenzyme, whose activity is highly dependent on polymorphism of the encoding gene. The objective of our study was to investigate the effects of CYP2C19*2 genetic polymorphisms on plasma and saliva concentrations of diazepam as well as its impact on the efficacy and safety rates of therapy in patients with AWS. The study was conducted on 100 Russian male patients with AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time polymerase chain reaction. The efficacy and safety assessment was performed using psychometric scales. We revealed differences in the efficacy and safety of therapy in patients with different CYP2C19 681G>A genotypes. Therapeutic drug monitoring (TDM) revealed the statistically significant differences in the levels of diazepam plasma concentration: (GG) 199.83 [82.92; 250.58] vs (GA+AA) 313.47 [288.99; 468.33], p=0.040, and diazepam saliva concentration: (GG) 2.80 [0.73; 3.80] vs (GA+AA) 5.33 [5.14; 6.00], p=0.003).

Highlights

Today benzodiazepines (BZDs) are among the most widely prescribed medicinal products in the world [1]
The CYP2C19 genotyping by polymorphic marker 681G>A performed in 100 patients have revealed the following:
The results of our study revealed the difference between the efficacy and safety profiles of diazepam in patients with alcohol withdrawal syndrome (AWS) carrying different genotypes of the CYP2C19 gene by polymorphic marker 681G>A

Summary

Introduction

Today benzodiazepines (BZDs) are among the most widely prescribed medicinal products in the world [1]. They have the largest and the best evidence base in the treatment of alcohol withdrawal syndrome (AWS), and are considered the gold standard [2]. According to the available scientific data, in a subset of patients, AWS worsens despite escalating doses of BZDs [3]. Such patients represent a severe alcohol withdrawal state and a serious challenge to practitioners due to the acuity and refractoriness of the disorder [4, 5]. The incidence rates of this state are unknown, but patients suffering from the resistant AWS were found to have a higher rate of intubation, longer ICU stays, and a greater risk of nosocomial infections in comparison with the patients with the AWS who Personalized Psychiatry and Neurology 2021, 1 (1)

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Results

Discussion

Conclusion