Br J Pharmacol. 2022 Jan 11. doi: 10.1111/bph.15795. Online ahead of print.
ABSTRACT
BACKGROUND AND PURPOSE: Acamprosate is an anti-craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, and to determine whether those differences might provide insight into variation in acamprosate treatment response phenotypes.
EXPERIMENTAL APPROACH: We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for the 3-month follow-up. The primary outcome was abstinence. Clinical information, genomic data, and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics.
RESULTS: Baseline plasma arginine, threonine, alpha-aminoadipic-acid, and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure which has been associated with acamprosate treatment response. We next applied a pharmacometabolomics-informed genome-wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. RNA-seq data for induced pluripotent stem cell-derived forebrain astrocytes showed that a series of genes identified during the metabolomics-informed GWAS were ethanol-responsive. Furthermore, a large number of those genes could also be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes.
CONCLUSION AND IMPLICATIONS: These results serve as an important step toward advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.
PMID:35016259 | DOI:10.1111/bph.15795
