沙沙利汀
化学
药理学
生物化学
半胱氨酸
谷胱甘肽
水飞蓟宾
代谢物
维尔达格利普汀
酶
医学
磷酸西他列汀
内分泌学
二甲双胍
糖尿病
作者
Kiyoung Kim,Yeo-jin Jeong,So‐Young Park,Eun-Ji Park,Ji-Hyeon Jeon,Im‐Sook Song,Kwang‐Hyeon Liu
标识
DOI:10.3390/pharmaceutics16010106
摘要
A liver injury was recently reported for saxagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor. However, the underlying mechanisms of saxagliptin-induced liver injury remain unknown. This study aimed to evaluate whether saxagliptin, a potent and selective DPP-4 inhibitor that is globally used for treating type 2 diabetes mellitus, binds to the nucleophiles in vitro. Four DPP-4 inhibitors, including vildagliptin, were evaluated for comparison. Only saxagliptin and vildagliptin, which both contain a cyanopyrrolidine group, quickly reacted with L-cysteine to enzyme-independently produce thiazolinic acid metabolites. This saxagliptin–cysteine adduct was also found in saxagliptin-administered male Sprague–Dawley rats. In addition, this study newly identified cysteinyl glycine conjugates of saxagliptin and 5-hydroxysaxagliptin. The observed metabolic pathways were hydroxylation and conjugation with cysteine, glutathione, sulfate, and glucuronide. In summary, we determined four new thiazoline-containing thiol metabolites (cysteine and cysteinylglycine conjugates of saxagliptin and 5-hydroxysaxagliptin) in saxagliptin-administered male rats. Our results reveal that saxagliptin can covalently bind to the thiol groups of cysteine residues of endogenous proteins in vivo, indicating the potential for saxagliptin to cause drug-induced liver injury.
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