Screening trimethoprim primary metabolites for covalent binding to albumin
Modification of endogenous proteins by drugs and drug metabolites are thought to be a cause of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP) is a commonly prescribed antibiotic that has been implicated in IADRs; however, there is no known mechanism by which this drug or its metabolites modify proteins. This study describes the results of screening trimethoprim and its primary metabolites for the ability to covalently modify human serum albumin (HSA). The first step of the screen was in vitro reactions of the compounds with HSA followed by western blotting with antisera specific to drug-modified proteins. Compounds with positive signal in the western blot were then screened using an untargeted peptide profiling method to discover modified peptides. This strategy identified two sites in HSA that are modified by incubation with a TMP metabolite, α-hydroxy trimethoprim (Cα-OH-TMP).
Med Chem Res
Trimethoprim; Metabolism; Protein Adduct; Adverse drug reaction
Nolte, W.M., Tessman, R.T. & Goldman, J.L. Screening trimethoprim primary metabolites for covalent binding to albumin. Med Chem Res 29, 1238–1246 (2020). https://doi.org/10.1007/s00044-020-02570-z