کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2479338 1113439 2009 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Quantitative Assessment of Reactive Metabolite Formation using 35S-labeled Glutathione
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
پیش نمایش صفحه اول مقاله
Quantitative Assessment of Reactive Metabolite Formation using 35S-labeled Glutathione
چکیده انگلیسی

Summary:The metabolic bioactivation of a drug to a reactive metabolite (RM) and its covalent binding to cellular macromolecules is believed to be involved in clinical adverse events, including idiosyncratic drug toxicities. Therefore, it is important to assess the potential of drug candidates to generate RMs and form drugprotein covalent adducts during lead optimization processes. In this study, the RM formation of some marketed drugs were quantitatively assessed by means of a sensitive and robust detection method that we have established using 35S-glutathione (35S-GSH) as a trapping agent. Problematic drugs well-known to generate RMs exhibited a relatively high rate of 35S-GS-adducts to RM (RM-GS) formation, which contrasted with safe drugs. For practical use in lead optimization processes, a series of new chemical entities were tested and hints on the structural modifications needed in order to minimize their RM formation were provided. Furthermore, the RM-GS formation rates of a number of compounds were compared using their in vitro covalent binding yields to liver proteins determined with 14C-labeled compounds, demonstrating that the RM-GS formation rate could be a substitute for the covalent binding yield within the same series of compounds.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Drug Metabolism and Pharmacokinetics - Volume 24, Issue 1, 2009, Pages 100-107