In Vitro Metabolism of Donepezil in Liver Microsomes Using Non-Targeted Metabolomics

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2021 Jul 2

PMID 34201744

Citations 3

Authors

Sin-Eun Kim

Hyung-Ju Seo

Yeojin Jeong

Gyung-Min Lee

Seung-Bae Ji

So-Young Park

Zhexue Wu

Sangkyu Lee

Sunghwan Kim

Kwang-Hyeon Liu

Affiliations

Soon will be listed here.

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) -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.

Citing Articles

Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular Networking.

Park E, Kim E, Kim K, Jeon J, Song I, Park S Pharmaceutics. 2025; 17(1).

PMID: 39861762 PMC: 11769037. DOI: 10.3390/pharmaceutics17010115.

Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats.

Kim K, Jeong Y, Park S, Park E, Jeon J, Song I Pharmaceutics. 2024; 16(1).

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The assessment of the potential hepatotoxicity of new drugs by metabolomics.

Quintas G, Castell J, Moreno-Torres M Front Pharmacol. 2023; 14:1155271.

PMID: 37214440 PMC: 10196061. DOI: 10.3389/fphar.2023.1155271.

Identifying xenobiotic metabolites with prediction tools and LCMS suspect screening analysis.

Boyce M, Favela K, Bonzo J, Chao A, Lizarraga L, Moody L Front Toxicol. 2023; 5:1051483.

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References

Alva G, Cummings J . Relative tolerability of Alzheimer's disease treatments. Psychiatry (Edgmont). 2009; 5(11):27-36. PMC: 2695725. View

Li F, Miao Y, Zhang L, Neuenswander S, Douglas J, Ma X . Metabolomic analysis reveals novel isoniazid metabolites and hydrazones in human urine. Drug Metab Pharmacokinet. 2011; 26(6):569-76. DOI: 10.2133/dmpk.DMPK-11-RG-055. View

Coin A, Pamio M, Alexopoulos C, Granziera S, Groppa F, De Rosa G . Donepezil plasma concentrations, CYP2D6 and CYP3A4 phenotypes, and cognitive outcome in Alzheimer's disease. Eur J Clin Pharmacol. 2016; 72(6):711-7. DOI: 10.1007/s00228-016-2033-1. View

Attia S . Deleterious effects of reactive metabolites. Oxid Med Cell Longev. 2010; 3(4):238-53. PMC: 2952084. DOI: 10.4161/oxim.3.4.13246. View

Tiseo P, Perdomo C, Friedhoff L . Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study. Br J Clin Pharmacol. 1998; 46 Suppl 1:19-24. PMC: 1873810. DOI: 10.1046/j.1365-2125.1998.0460s1019.x. View

Sun J, Von Tungeln L, Hines W, Beger R . Identification of metabolite profiles of the catechol-O-methyl transferase inhibitor tolcapone in rat urine using LC/MS-based metabonomics analysis. J Chromatogr B Analyt Technol Biomed Life Sci. 2009; 877(24):2557-65. DOI: 10.1016/j.jchromb.2009.06.033. View

Matsui K, Mishima M, Nagai Y, Yuzuriha T, Yoshimura T . Absorption, distribution, metabolism, and excretion of donepezil (Aricept) after a single oral administration to Rat. Drug Metab Dispos. 1999; 27(12):1406-14. View

Kim J, Choi W, Moon J, Lee J, Lee S, Lee H . Metabolomics-assisted metabolite profiling of itraconazole in human liver preparations. J Chromatogr B Analyt Technol Biomed Life Sci. 2018; 1083:68-74. DOI: 10.1016/j.jchromb.2018.02.041. View

Argoti D, Liang L, Conteh A, Chen L, Bershas D, Yu C . Cyanide trapping of iminium ion reactive intermediates followed by detection and structure identification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Chem Res Toxicol. 2006; 18(10):1537-44. DOI: 10.1021/tx0501637. View

10.

Jian W, Liu H, Zhao W, Jones E, Zhu M . Simultaneous screening of glutathione and cyanide adducts using precursor ion and neutral loss scans-dependent product ion spectral acquisition and data mining tools. J Am Soc Mass Spectrom. 2012; 23(5):964-76. DOI: 10.1007/s13361-012-0354-6. View

11.

Bolleddula J, DeMent K, Driscoll J, Worboys P, Brassil P, Bourdet D . Biotransformation and bioactivation reactions of alicyclic amines in drug molecules. Drug Metab Rev. 2014; 46(3):379-419. DOI: 10.3109/03602532.2014.924962. View

12.

Yu J, Seo H, Kim G, Hong J, Hyun Yoo H . MS-Based Molecular Networking of Designer Drugs as an Approach for the Detection of Unknown Derivatives for Forensic and Doping Applications: A Case of NBOMe Derivatives. Anal Chem. 2019; 91(9):5483-5488. DOI: 10.1021/acs.analchem.9b00294. View

13.

Tanaka A, Koga S, Hiramatsu Y . Donepezil-induced adverse side effects of cardiac rhythm: 2 cases report of atrioventricular block and Torsade de Pointes. Intern Med. 2009; 48(14):1219-23. DOI: 10.2169/internalmedicine.48.2181. View

14.

Verrico M, Nace D, Towers A . Fulminant chemical hepatitis possibly associated with donepezil and sertraline therapy. J Am Geriatr Soc. 2000; 48(12):1659-63. DOI: 10.1111/j.1532-5415.2000.tb03879.x. View

15.

Joo J, Wu Z, Lee B, Shon J, Lee T, Lee I . In vitro metabolism of an estrogen-related receptor γ modulator, GSK5182, by human liver microsomes and recombinant cytochrome P450s. Biopharm Drug Dispos. 2014; 36(3):163-73. DOI: 10.1002/bdd.1929. View

16.

Li F, Lu J, Ma X . Profiling the reactive metabolites of xenobiotics using metabolomic technologies. Chem Res Toxicol. 2011; 24(5):744-51. PMC: 3100669. DOI: 10.1021/tx200033v. View

17.

Baillie T, Rettie A . Role of biotransformation in drug-induced toxicity: influence of intra- and inter-species differences in drug metabolism. Drug Metab Pharmacokinet. 2010; 26(1):15-29. PMC: 4675351. DOI: 10.2133/dmpk.dmpk-10-rv-089. View

18.

Strolin Benedetti M, Whomsley R, Poggesi I, Cawello W, Mathy F, Delporte M . Drug metabolism and pharmacokinetics. Drug Metab Rev. 2009; 41(3):344-90. DOI: 10.1080/10837450902891295. View

19.

Zhang Z, Tang W . Drug metabolism in drug discovery and development. Acta Pharm Sin B. 2018; 8(5):721-732. PMC: 6146880. DOI: 10.1016/j.apsb.2018.04.003. View

20.

Almazroo O, Miah M, Venkataramanan R . Drug Metabolism in the Liver. Clin Liver Dis. 2016; 21(1):1-20. DOI: 10.1016/j.cld.2016.08.001. View