Pharmacogenetic Impact of CYP2C19 Variants on Diazepam Treatment Outcomes in Alcohol Withdrawal Syndrome.

Diazepam (DZP) is widely accepted as an effective pharmaceutical intervention for treating Alcohol Withdrawal Syndrome (AWS), and its efficacy and metabolic profile are influenced by genetic variations in the CYP2C19 gene. The objective of the present study was to investigate the impact of the CYP2C19*2 and CYP2C19*17 phenotypes on DZP metabolism. Whole blood samples were collected from 114 patients with AWS following a 10-day course of oral DZP therapy. Genotyping was performed using PCR-RFLP. Plasma concentrations of DZP and nordiazepam (NDZP) were determined using HPLC-UV. The CYP2C19*17 TT genotype (1.597 ± 0.589) showed a significantly higher metabolic ratio (MR) compared to CC (1.159 ± 0.423) and CT (1.374 ± 0.368) genotypes (p = 0.015). Withdrawal severity after treatment was significantly lower in TT carriers than in CC and CT genotypes (p = 0.043). Pharmacokinetic and clinical parameters varied across CYP2C19 diplotypes, with ultrarapid (*17/*17) and rapid (*1/*17) metabolisers demonstrating higher MR and lower withdrawal severity compared to extensive metabolisers (*1/*1). The CYP2C19*2 haplotype was associated with higher dose-normalised DZP concentrations, whereas CYP2C19*17 was associated with a higher metabolic ratio. This study is the first to quantify plasma DZP and NDZP levels after 10-day oral administration and link them to CYP2C19*2 and CYP2C19*17 genotypes, haplotypes and diplotypes. The metabolic ratio (NDZP/DZP) emerged as a more integrative indicator of CYP2C19 activity than absolute levels, highlighting the complex genotype-phenotype relationship in DZP metabolism. Notably, the CYP2C19*17 gain-of-function allele significantly was associated with increased metabolic efficiency and improved clinical outcomes in AWS.