Nakayama, Shintaro published the artcileCombination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites, Quality Control of 40180-04-9, the main research area is glutathione trapping covalent binding liver microsome reactive metabolite pharmacokinetics.
Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qual. trapping assay using agents such as [35S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [35S]GSH trapping assay in detecting RMs. We performed CB assays, [35S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds First, we showed that the [35S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [35S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as pos. in the TDI assay to show a high degree of CB irresp. of the result of the [35S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CLint, RMs). The Spearman rank correlation coefficient between the extent of CB and CLint, RMs was 0.77 (p < 0.0001), which was better than that for the formation rates of [35S]GSH adducts. Therefore, we demonstrated that a combination of the [35S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery. Drug Metabolism and Disposition published new progress about Homo sapiens. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Quality Control of 40180-04-9.
Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem