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).

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筛选甲氧苄啶初级代谢产物与白蛋白的共价结合

药物和药物代谢物对内源蛋白质的修饰被认为是特异药物不良反应（IADR）的原因。甲氧苄氨嘧啶（TMP）是一种常见的抗生素，与IADR有关。但是，尚不知道该药物或其代谢物修饰蛋白质的机制。这项研究描述了筛选甲氧苄啶及其主要代谢产物共价修饰人血清白蛋白（HSA）的能力的结果。筛选的第一步是化合物与HSA的体外反应，然后用对药物修饰的蛋白质具有特异性的抗血清进行蛋白质印迹。然后使用非靶向肽谱分析方法筛选在蛋白质印迹中具有阳性信号的化合物，以发现修饰的肽。