Kim Sin-Eun, Seo Hyung-Ju, Jeong Yeojin, Lee Gyung-Min, Ji Seung-Bae, Park So-Young, Wu Zhexue, Lee Sangkyu, Kim Sunghwan, Liu Kwang-Hyeon
BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
Mass Spectrometry Based Convergence Research Institute, Kyungpook National University, Daegu 41566, Korea.
Pharmaceutics. 2021 Jun 23;13(7):936. doi: 10.3390/pharmaceutics13070936.
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) -demethylation, (2) hydroxylation, (3) -oxidation, and (4) -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.
多奈哌齐是一种可逆性乙酰胆碱酯酶抑制剂，目前是治疗阿尔茨海默病最常用的处方药。一般来说，多奈哌齐是一种安全且耐受性良好的药物，在多项临床试验中它与肝脏异常无关。然而，自其上市以来，已有罕见的药物相关肝毒性病例报告。很少有研究调查多奈哌齐的代谢谱，且多奈哌齐引起肝损伤的机制尚未阐明。在本研究中，基于非靶向代谢组学方法，采用液相色谱 - 串联质谱法研究了多奈哌齐的体外代谢。为鉴定代谢物，对数据进行了多变量数据分析和分子网络分析。共检测到21种多奈哌齐代谢物（人肝微粒体中17种、小鼠肝微粒体中21种、大鼠肝微粒体中17种），包括14种新鉴定的代谢物。在大鼠肝微粒体孵育样品中鉴定出一种潜在的反应性代谢物。代谢物通过四种主要代谢途径形成：（1）N - 去甲基化，（2）羟基化，（3）ω - 氧化，和（4）O - 去苄基化。本研究表明，非靶向代谢组学方法与分子网络分析相结合是鉴定和检测未知药物代谢物的可靠工具。
