Applications of Mass Spectrometry in Elucidating Human Drug Metabolism: From the Preclinical Phase to Real-World Studies

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Pharmacology and Drug Metabolism".

Deadline for manuscript submissions: 1 March 2026 | Viewed by 555

Special Issue Editor


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Guest Editor
Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Interests: drug metabolism; exposomics; liquid chromatography; mass spectrometry; metabolite profiling; metabolomics; personalized medicine; pharmacogenetics; pharmacometabolomics; pharmacy

Special Issue Information

Dear Colleagues,

Elucidation of human drug metabolism is key to the development of effective and safe therapeutics and, furthermore, forms the basis of therapeutic drug monitoring and pharmacogenetic testing. This elucidation work spans multiple stages of drug development, notably during the preclinical phase through in vitro (e.g., microsomes, hepatocytes), ex vivo (e.g., precision-cut liver slices), and in vivo (e.g., animal studies) experiments, as well as the clinical phase via human radiolabeled mass balance studies. Recent advancements in small-molecule profiling have further expanded the utility of these approaches in real-world settings, supporting the transition towards more personalized pharmacotherapy.

This Special Issue of Metabolites aims to highlight novel fundamental and clinical applications of mass spectrometry in characterizing drug metabolism, from preclinical studies to post-marketing clinical studies. We invite contributions across a broad range of topics, including (pharma) cometabolomics, toxicokinetics, pharmacophenotyping, and integrative research focused on mapping and understanding inter-individual variability in pharmacokinetics and drug response. Studies leveraging cutting-edge analytical platforms to investigate metabolic pathways, describe understudied xenobiotic conversion reactions, and improve therapeutic outcomes are particularly welcome.

Dr. Frank Klont
Guest Editor

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Keywords

  • drug metabolism
  • liquid chromatography
  • mass balance studies
  • mass spectrometry
  • metabolite profiling
  • metabolomics
  • personalized medicine
  • pharmacogenetics
  • pharmacometabolomics
  • pharmacy

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Published Papers (1 paper)

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Research

26 pages, 2295 KB  
Article
Retrospective Urine Metabolomics of Clinical Toxicology Samples Reveals Features Associated with Cocaine Exposure
by Rachel K. Vanderschelden, Reya Kundu, Delaney Morrow, Simmi Patel and Kenichi Tamama
Metabolites 2025, 15(9), 563; https://doi.org/10.3390/metabo15090563 - 22 Aug 2025
Viewed by 367
Abstract
Background/Objectives: Cocaine is a widely used illicit stimulant with significant toxicity. Despite its clinical relevance, the broader metabolic alterations associated with cocaine use remain incompletely characterized. This study aims to identify novel biomarkers for cocaine exposure by applying untargeted metabolomics to retrospective urine [...] Read more.
Background/Objectives: Cocaine is a widely used illicit stimulant with significant toxicity. Despite its clinical relevance, the broader metabolic alterations associated with cocaine use remain incompletely characterized. This study aims to identify novel biomarkers for cocaine exposure by applying untargeted metabolomics to retrospective urine drug screening data. Methods: We conducted a retrospective analysis of a raw mass spectrometry (MS) dataset from urine comprehensive drug screening (UCDS) from 363 patients at the University of Pittsburgh Medical Center Clinical Toxicology Laboratory. The liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-qToF-MS) data were preprocessed with MS-DIAL and subjected to multiple statistical analyses to identify features significantly associated with cocaine-enzyme immunoassay (EIA) results. Significant features were further evaluated using MS-FINDER for feature annotation. Results: Among 14,883 features, 262 were significantly associated with cocaine-EIA results. A subset of 37 more significant features, including known cocaine metabolites and impurities, nicotine metabolites, norfentanyl, and a tryptophan-related metabolite (3-hydroxy-tryptophan), was annotated. Cluster analysis revealed co-varying features, including parent compounds, metabolites, and related ion species. Conclusions: Features associated with cocaine exposure, including previously underrecognized cocaine metabolites and impurities, co-exposure markers, and alterations in an endogenous metabolic pathway, were identified. Notably, norfentanyl was found to be significantly associated with cocaine -EIA, reflecting current trends in illicit drug use. This study highlights the potential of repurposing real-world clinical toxicology data for biomarker discovery, providing a valuable approach to identifying exposure biomarkers and expanding our understanding of drug-induced metabolic disturbances in clinical toxicology. Further validation and exploration using complementary analytical platforms are warranted. Full article
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