Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular Networking
<b>Background/Objectives</b>: 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–...
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| author | Eun-Ji Park Eui-Hyeon Kim Ki-Young Kim Ji-Hyeon Jeon Im-Sook Song So-Young Park Kwang-Hyeon Liu |
| author_facet | Eun-Ji Park Eui-Hyeon Kim Ki-Young Kim Ji-Hyeon Jeon Im-Sook Song So-Young Park Kwang-Hyeon Liu |
| author_sort | Eun-Ji Park |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: 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. <b>Methods</b>: 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. <b>Results</b>: A total of 50 metabolites were characterized, including 23 newly identified metabolites. Donepezil was biotransformed by <i>O-</i>demethylation, <i>N-</i>debenzylation, and hydroxylation, and these metabolites are further conjugated with glucuronic acid and sulfurous acid. <i>N-</i>Desbenzyldonepezil (<b>M4</b>), didesmethyldonepezil (<b>M5</b>), and <i>N-</i>desbenzyldonepezil (<b>M4</b>) were identified as the most abundant metabolites in urine, feces, and liver samples, respectively. <b>Conclusions</b>: 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. |
| format | Article |
| id | doaj-art-7de7594d2ec1404596bbdb9a364b4a3f |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-7de7594d2ec1404596bbdb9a364b4a3f2025-01-24T13:46:01ZengMDPI AGPharmaceutics1999-49232025-01-0117111510.3390/pharmaceutics17010115Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular NetworkingEun-Ji Park0Eui-Hyeon Kim1Ki-Young Kim2Ji-Hyeon Jeon3Im-Sook Song4So-Young Park5Kwang-Hyeon Liu6BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of KoreaBK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of KoreaBK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of KoreaBK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of KoreaBK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of KoreaBK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of KoreaBK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea<b>Background/Objectives</b>: 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. <b>Methods</b>: 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. <b>Results</b>: A total of 50 metabolites were characterized, including 23 newly identified metabolites. Donepezil was biotransformed by <i>O-</i>demethylation, <i>N-</i>debenzylation, and hydroxylation, and these metabolites are further conjugated with glucuronic acid and sulfurous acid. <i>N-</i>Desbenzyldonepezil (<b>M4</b>), didesmethyldonepezil (<b>M5</b>), and <i>N-</i>desbenzyldonepezil (<b>M4</b>) were identified as the most abundant metabolites in urine, feces, and liver samples, respectively. <b>Conclusions</b>: 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.https://www.mdpi.com/1999-4923/17/1/115donepezilmass spectrometrymetabolismmolecular networkingnontargeted metabolomics |
| spellingShingle | Eun-Ji Park Eui-Hyeon Kim Ki-Young Kim Ji-Hyeon Jeon Im-Sook Song So-Young Park Kwang-Hyeon Liu Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular Networking Pharmaceutics donepezil mass spectrometry metabolism molecular networking nontargeted metabolomics |
| title | Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular Networking |
| title_full | Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular Networking |
| title_fullStr | Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular Networking |
| title_full_unstemmed | Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular Networking |
| title_short | Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular Networking |
| title_sort | revisiting the metabolism of donepezil in rats using non targeted metabolomics and molecular networking |
| topic | donepezil mass spectrometry metabolism molecular networking nontargeted metabolomics |
| url | https://www.mdpi.com/1999-4923/17/1/115 |
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