Identification of a novel metabolite of vildagliptin in humans: Cysteine targets the nitrile moiety to form a thiazoline ring

Biochemical Pharmacology
Katsuhiko MizunoMiki Nakajima

Abstract

The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin (VG) is used to treat type 2 diabetes. In rare cases, VG-induced liver injury has been reported. One case report suggested that immune responses were involved in the hepatotoxicity. However, the underlying mechanisms of VG-induced hepatotoxicity are uncertain. In the present study, we investigated whether VG has the potential to covalently bind to macromolecules in cells, a process that could initiate immune-mediated hepatotoxicity. For comparison, M20.7, a major metabolite of VG, and other DPP-4 inhibitors were also evaluated. We found that VG and anagliptin (ANG), which both contain a cyanopyrrolidine moiety, rapidly reacted in non-enzymatic manners on co-incubation with l-cysteine. Both VG and ANG had half-lives of 20-30 min. In contrast, incubation with GSH, rather than l-cysteine, failed to decrease the concentrations of VG or ANG. M20.7, sitagliptin, linagliptin, and alogliptin, having no cyanopyrrolidine moiety, were stable on incubation with l-cysteine or GSH. Structural analysis of the VG- and ANG-cysteine adducts, designated M407 and M487, respectively, revealed that the nitrile moieties of VG and ANG were irreversibly converted to a thiazoline acid. In conclus...Continue Reading

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