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

Author

Listed:
  • Tara J. Bowen

    (University of Birmingham)

  • Andrew D. Southam

    (University of Birmingham
    University of Birmingham)

  • Andrew R. Hall

    (BioPharmaceuticals R&D, AstraZeneca)

  • Ralf J. M. Weber

    (University of Birmingham
    University of Birmingham)

  • Gavin R. Lloyd

    (University of Birmingham)

  • Ruth Macdonald

    (BioPharmaceuticals R&D, AstraZeneca)

  • Amanda Wilson

    (BioPharmaceuticals R&D, AstraZeneca)

  • Amy Pointon

    (BioPharmaceuticals R&D, AstraZeneca)

  • Mark R. Viant

    (University of Birmingham
    University of Birmingham)

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.

Suggested Citation

  • 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, 2023. "Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40333-7
    DOI: 10.1038/s41467-023-40333-7
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    as
    1. Mark R. Viant & Timothy M. D. Ebbels & Richard D. Beger & Drew R. Ekman & David J. T. Epps & Hennicke Kamp & Pim E. G. Leonards & George D. Loizou & James I. MacRae & Bennard Ravenzwaay & Philippe Roc, 2019. "Use cases, best practice and reporting standards for metabolomics in regulatory toxicology," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
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