Short-term standard alcohol consumption enhances platelet response to clopidogrel through inhibition of Nrf2/Ces1 pathway and induction of Cyp2c in mice

• Published in: Life sciences (1973) Vol. 279; p. 119268
• Main Authors: Ge, Peng-Xin, Jiang, Li-Ping, Tai, Ting, Zhu, Ting, Ji, Jin-Zi, Li, Yi-Fei, Mi, Qiong-Yu, Xie, Hong-Guang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.08.2021; Elsevier BV
• Subjects: Agglomeration; Alcohol; Alcohol use; Alcohols; Carboxylesterase 1; Clopidogrel; CYP2C; Drinking behavior; Drug-alcohol interaction; Gene expression; Metabolic activation; Metabolic rate; Metabolism; Metabolites; mRNA; Nrf2; Platelet; Platelet aggregation; Signal transduction; EtOH; Alcohol; ADP; AUC; LC-MS/MS; MFI; CYP (for humans); Nrf2; Ces 1; AUC0-t; Cmax; qRT-PCR; Drug-alcohol interaction; IS; Carboxylesterase 1; H4; CLP-C; CYP2C; Platelet; t; AUC0-; Tmax; Keap1; Clopidogrel; BHA; MPB
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.119268

Drinking alcohol is prevalent worldwide; however, it is unknown whether alcohol could affect the antiplatelet effects of clopidogrel in patients when taking both concomitantly. This study was designed to investigate the influence of short-term standard alcohol consumption on the metabolic activation of and platelet response to clopidogrel in mice as well as the mechanisms involved. Male C57BL/6J mice were administered with normal saline (vehicle control) or alcohol at 2 g/kg/day for 7 days, and then gavaged with vehicle control or a single dose of clopidogrel at 10 mg/kg. Inhibition of ADP-induced platelet aggregation and activation by clopidogrel, plasma concentrations of clopidogrel and its active metabolite H4, and changes in mRNA and protein expression of genes related to clopidogrel metabolism and its regulation were measured in mice pretreated with or without alcohol. Compared with vehicle control, alcohol pretreatment significantly reduced hydrolysis of clopidogrel as a result of significant down-regulation of Nrf2-mediated Ces1 expression (responsible for the formation of clopidogrel carboxylate), increased metabolic activation of clopidogrel due to significant up-regulation of Cyp2c (for the formation of active thiol metabolite H4), and consequently enhanced inhibition of ADP-induced platelet aggregation and activation by clopidogrel. Short-term standard alcohol consumption would significantly enhance suppression of ADP-induced platelet aggregation and activation by clopidogrel through significant inhibition of Nrf2/Ces1 signaling pathway and induction of Cyp2c, suggesting that alcohol may interact with drugs that are predominantly metabolized by CES1 or CYP2C in patient care, including clopidogrel. [Display omitted] •Short-term standard alcohol consumption suppresses Nrf2/Ces1 signaling pathway.•Short-term standard alcohol consumption induces Cyp2c expression and activity.•Alcohol pretreatment enhances platelet response to clopidogrel coordinately.•Despite potential benefits, concomitant use of alcohol and clopidogrel is not recommended.•Alcohol interacts with drugs that are metabolized predominantly by CYP2C or CES1.