: Although donepezil, a reversible acetylcholinesterase inhibitor, has been in use since 1996, its metabolic characteristics remain poorly characterized. Therefore, this study aims to investigate the in vivo metabolism of donepezil using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) based on a molecular networking (MN) approach integrated with a non-targeted metabolomics approach. : After the oral administration of donepezil (30 mg/kg) in rats, urine, feces, and liver samples were collected for LC-HRMS analysis. Chromatographic and spectrometric data were processed through MN and multivariate data analysis to identify the in vivo metabolites of donepezil. : A total of 50 metabolites were characterized, including 23 newly identified metabolites. Donepezil was biotransformed by demethylation, debenzylation, and hydroxylation, and these metabolites are further conjugated with glucuronic acid and sulfurous acid. Desbenzyldonepezil (), didesmethyldonepezil (), and desbenzyldonepezil () were identified as the most abundant metabolites in urine, feces, and liver samples, respectively. : The metabolic characteristics of donepezil in rats were comparable to those in humans, indicating that a rat is a reliable model for studying donepezil metabolism. This study indicates that a MN approach combined with a metabolomics approach is a reliable tool to identify unknown metabolites of drugs and drug candidates.
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