Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics

Tara J. Bowen, Andrew D. Southam, Andrew R. Hall, Ralf J. M. Weber, Gavin R. Lloyd, Ruth Macdonald, Amanda Wilson, Amy Pointon, Mark R. Viant*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated. Here we assemble a workflow to discover and analyse pharmaceutical-related measurements from routine untargeted UHPLC-MS metabolomics datasets, derived from in vivo (rat plasma and cardiac tissue, and human plasma) and in vitro (human cardiomyocytes) studies that were principally designed to investigate endogenous metabolic responses to drug exposure. Our findings clearly demonstrate how untargeted metabolomics can discover extensive biotransformation maps, temporally-changing relative systemic exposure, and direct associations of endogenous biochemical responses to the internal dose.
Original languageEnglish
Article number4653
Number of pages18
JournalNature Communications
Volume14
Issue number1
Early online date3 Aug 2023
DOIs
Publication statusPublished - Dec 2023

Bibliographical note

Funding Information:
We gratefully acknowledge the contribution to this publication made by the University of Birmingham’s Human Biomaterials Resource Centre which has been supported through Birmingham Science City—Experimental Medicine Network of Excellence project. The authors thank Thermo Fisher Scientific for their support of this project via the University of Birmingham—Thermo Fisher Scientific Technology Alliance Partnership. We also thank Dr. Lukáš Najedkr and Dr. Andris Jankevics (Phenome Centre Birmingham, UK) for their scientific advice. We thank the BBSRC (BB/S507064/1) and AstraZeneca for funding this project via a PhD studentship awarded to T.J.B.

Publisher Copyright:
© 2023, The Author(s).

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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