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Updated: Jan 10, 2026

Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
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Metabolism Profiles of Trimethoprim in Idiosyncratic Adverse Drug Reaction-Affected Tissues

Robert T Tessman1, Whitney Nolte1, Priscilla Flores-Ascencio1

  • 1Division of Clinical Pharmacology, Children's Mercy Research Institute, Toxicology and Therapeutic Innovation. 2401 Gillham Rd, Kansas City, Missouri 64108, United States.

Chemical Research in Toxicology
|November 20, 2025
PubMed

Insights

Trimethoprim (TMP) metabolism varies by organ. Phase I metabolites form mainly in the liver, while Phase II metabolites appear in other tissues, aiding understanding of TMP adverse drug reactions.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Toxicology

Background:

  • Trimethoprim (TMP) is a vital antibiotic, often combined with sulfamethoxazole.
  • Idiosyncratic adverse drug reactions (IADRs) to TMP, including skin rashes, lung issues, and liver damage, affect a subset of patients.
  • Limited understanding of TMP metabolism hinders the elucidation of TMP-IADR mechanisms.

Purpose of the Study:

  • To investigate Trimethoprim (TMP) phase I and II metabolism in human liver, lung, and skin tissues.
  • To identify TMP metabolites in urine from individuals tolerating TMP treatment.
  • To correlate TMP metabolic pathways with tissues implicated in IADRs.

Main Methods:

  • Utilized human s9 subcellular fractions from liver, lung, and skin.
  • Employed triple-quadrupole and quadrupole-time-of-flight mass spectrometry for metabolite identification and quantification.
  • Analyzed urine samples from TMP-tolerant subjects.

Main Results:

  • Phase I TMP metabolism predominantly occurs in the liver.
  • Phase II TMP metabolites exhibit differential formation in extrahepatic tissues (lung, skin).
  • Identified TMP metabolites were detected in urine samples.

Conclusions:

  • Characterized TMP phase I and II metabolism across key tissues involved in IADRs.
  • Provides a foundational understanding of TMP metabolic distribution relevant to IADR etiology.
  • This metabolic profiling is crucial for advancing research into TMP-induced adverse drug reactions.

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