ArticleChemical research in toxicology2025
Metabolism Profiles of Trimethoprim in Idiosyncratic Adverse Drug Reaction-Affected Tissues.
Article in Chemical research in toxicology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Trimethoprim (TMP) is an essential antibiotic used in combination with sulfamethoxazole to treat and prevent bacterial infections. Idiosyncratic adverse drug reactions (IADRs) to TMP occur in a small but significant percentage of the treatment population. TMP IADRs manifest as mild to life-threatening skin rashes, pulmonary failure, or hepatotoxicity. Currently, our incomplete knowledge of TMP metabolism is a barrier to understanding the TMP-IADR etiology. In this study, we investigated TMP phase I and II metabolism in tissues involved with IADRs including liver, lung, and skin using human s9 subcellular fractions. Triple-quadrupole and quadrupole-time-of-flight mass spectrometry were used to compare trimethoprim phase I and phase II metabolism in these organ systems and to detect identified metabolites in the urine of subjects taking and tolerating TMP. In this study, we found that phase I TMP metabolites are formed predominantly in the liver, and phase II TMP metabolites are formed differentially in extrahepatic tissues. This characterization of TMP metabolism in affected tissues is an important step toward a better understanding of the mechanisms involved in the TMP IADRs.
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