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Metabolomic Analysis of Rat Brain by High Resolution Nuclear Magnetic Resonance Spectroscopy of Tissue Extracts
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Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular Networking.

Eun-Ji Park1, Eui-Hyeon Kim1, Ki-Young Kim1

  • 1BK21 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.

Pharmaceutics
|January 25, 2025
PubMed
Summary

This study characterized 50 donepezil metabolites in rats using molecular networking and metabolomics. Rat models accurately reflect human metabolism, validating this approach for drug discovery.

Keywords:
donepezilmass spectrometrymetabolismmolecular networkingnontargeted metabolomics

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Area of Science:

  • Pharmacology
  • Metabolomics
  • Analytical Chemistry

Background:

  • Donepezil, an acetylcholinesterase inhibitor, has limited characterized metabolic data.
  • Understanding donepezil metabolism is crucial for optimizing its therapeutic use.

Purpose of the Study:

  • To investigate the in vivo metabolism of donepezil in rats.
  • To identify donepezil metabolites using liquid chromatography-high-resolution mass spectrometry (LC-HRMS).
  • To evaluate molecular networking (MN) integrated with non-targeted metabolomics for metabolite identification.

Main Methods:

  • Oral administration of donepezil (30 mg/kg) to rats.
  • Collection and LC-HRMS analysis of urine, feces, and liver samples.
  • Processing data using MN and multivariate analysis for metabolite identification.

Main Results:

  • Characterized 50 donepezil metabolites, including 23 novel ones.
  • Identified key biotransformations: O-demethylation, N-debenzylation, and hydroxylation, followed by glucuronidation and sulfation.
  • N-Desbenzyldonepezil (M4) and didesmethyldonepezil (M5) were major metabolites in different sample types.

Conclusions:

  • Rat metabolism of donepezil is comparable to human metabolism, establishing rats as a suitable model.
  • The combined MN and metabolomics approach is effective for identifying unknown drug metabolites.
  • This methodology aids in the discovery of new drug candidates.