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Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
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Related Experiment Video

Updated: Jun 27, 2026

An All-Human Hepatic Culture System for Drug Development Applications
07:23

An All-Human Hepatic Culture System for Drug Development Applications

Published on: October 20, 2023

Characterization of Atrasentan Metabolic Pathway in Human Liver Microsomes Using Feature-Based Molecular Networking.

Hyung-Ju Seo1, Zhuoning Liang1, Eui-Hyeon Kim2

  • 1BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.

Pharmaceutics
|June 26, 2026
PubMed
Summary

This study identified 18 atrasentan metabolites in human liver microsomes, revealing a potential bioactivation pathway involving reactive intermediates. Further in vivo studies are needed to assess drug-induced liver injury risks.

Keywords:
atrasentancharacterizationdrug-induced liver injuryfeature-based molecular networkingmetabolismreactive metabolite

Related Experiment Videos

Last Updated: Jun 27, 2026

An All-Human Hepatic Culture System for Drug Development Applications
07:23

An All-Human Hepatic Culture System for Drug Development Applications

Published on: October 20, 2023

Area of Science:

  • Pharmacology and Toxicology
  • Drug Metabolism and Pharmacokinetics
  • Medicinal Chemistry

Background:

  • Atrasentan, a selective endothelin A receptor antagonist, shows promise for chronic kidney diseases.
  • Understanding atrasentan's metabolic bioactivation is crucial for evaluating drug-induced liver injury (DILI) risks.
  • The metabolic profile and hepatotoxicity mechanisms of atrasentan are not well-characterized.

Purpose of the Study:

  • To investigate the metabolic pathways of atrasentan in human liver microsomes (HLMs).
  • To identify metabolites formed via phase I and II reactions using various cofactors (NADPH, UDPGA, GSH).
  • To explore potential bioactivation pathways and their implications for hepatotoxicity.

Main Methods:

  • Utilized liquid chromatography-high resolution mass spectrometry (LC-HRMS) coupled with feature-based molecular networking.
  • Employed cytochrome P450 (P450) phenotyping with human recombinant P450 isoforms for metabolite characterization.
  • Incubated atrasentan with HLMs in the presence of NADPH, UDPGA, or GSH.

Main Results:

  • Characterized eighteen metabolites, including demethylenation, N-dealkylation, O-demethylation, hydroxylation, dehydrogenation, and glucuronidation products.
  • Identified atrasentan acyl glucuronide (M8) as the predominant metabolite.
  • Putatively identified a catechol intermediate (M5) and its glutathione (GSH) conjugate (M15), suggesting a potential bioactivation pathway via an ortho-quinone intermediate, primarily catalyzed by CYP3A subfamily.

Conclusions:

  • Feature-based molecular networking is effective for atrasentan metabolite identification.
  • A potential bioactivation pathway involving reactive intermediates was identified.
  • Further in vivo studies are essential to definitively assess the hepatotoxic risks associated with these reactive metabolites.