1. Academic Validation
  2. Identification of a novel metabolite of vildagliptin in humans: Cysteine targets the nitrile moiety to form a thiazoline ring

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

  • Biochem Pharmacol. 2018 Oct;156:312-321. doi: 10.1016/j.bcp.2018.08.043.
Katsuhiko Mizuno 1 Kenji Takeuchi 2 Ken Umehara 3 Miki Nakajima 4
Affiliations

Affiliations

  • 1 Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: Mizuno.Katsuhiko@otsuka.jp.
  • 2 Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
  • 3 Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
  • 4 Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
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 conclusion, we found that VG and ANG have the potential to covalently bind to a thiol residue of l-cysteine in proteins. Such binding may lead to unpredictable immune responses in humans. l-Cysteine, rather than GSH, would likely be useful to detect the potential for covalent binding that could initiate immune-mediated hepatotoxicity.

Keywords

Covalent binding; Drug-induced liver injury; Hypersensitivity; Nucleophilic trapping agents; Vildagliptin.

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