Abstract
Donepezil is a reversible acetylcholinesterase inhibitor that is currently the most commonly prescribed drug for the treatment of Alzheimer’s disease. In general, donepezil is known as a safe and well-tolerated drug, and it was not associated with liver abnormalities in several clinical trials. However, rare cases of drug-related liver toxicity have been reported since it has become commercially available. Few studies have investigated the metabolic profile of donepezil, and the mechanism of liver damage caused by donepezil has not been elucidated. In this study, the in vitro metabolism of donepezil was investigated using liquid chromatography–tandem mass spectrometry based on a non-targeted metabolomics approach. To identify metabolites, the data were subjected to multivariate data analysis and molecular networking. A total of 21 donepezil metabolites (17 in human liver microsomes, 21 in mice liver microsomes, and 17 in rat liver microsomes) were detected including 14 newly identified metabolites. One potential reactive metabolite was identified in rat liver microsomal incubation samples. Metabolites were formed through four major metabolic pathways: (1) O-demethylation, (2) hydroxylation, (3) N-oxidation, and (4) N-debenzylation. This study indicates that a non-targeted metabolomics approach combined with molecular networking is a reliable tool to identify and detect unknown drug metabolites.
Highlights
Drug metabolism makes it easier for the body to remove drugs by making them more hydrophilic [1]
We investigated the Phase I metabolism of donepezil using human liver microsomes (HLM), mouse liver microsomes (MLM), and rat liver microsomes (RLM)
A non-targeted metabolomics combined with molecular working using
Summary
Drug metabolism makes it easier for the body to remove drugs by making them more hydrophilic [1]. Metabolism consists of Phase I and Phase II reactions. The Phase II reactions consist of conjugating molecules, such as glucuronic acid, sulfate, glutathione, amino acids, methyl groups, and acetyl groups, to the compound itself or metabolites generated from the introduction of polar functional groups into the parent compound through Phase I reactions [2]. The pharmacological activity of most drugs is lost through metabolism. Metabolism can still produce active metabolites and, in some cases, reactive or toxic metabolites that may affect drug safety [3,4,5,6]. It is important to identify all of the drug metabolites in biological samples, such as urine, feces, and liver microsomes, which contain xenobiotic-metabolizing enzymes
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