Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases

doi:10.1124/dmd.118.084640

	Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases
	Kong, Fandi 1,2; Pang, Xiaoyan 1; Zhao, Jihui3 ; Deng, Pan 1; Zheng, Mingyue 1,2; Zhong, Dafang 1,2; Chen, Xiaoyan 1,2
	2019-03
发表期刊	DRUG METABOLISM AND DISPOSITION (IF:4.4[JCR-2023],3.7[5-Year])
ISSN	0090-9556
卷号	47 期号:3 页码:238-248
发表状态	已发表
DOI	10.1124/dmd.118.084640
摘要	Nitrile group biotransformation is an unusual or minor metabolic pathway for most nitrile-containing drugs. However, for some cyanopyrrolidine dipeptidyl peptidase 4 (DPP-4) inhibitors (vildagliptin, anagliptin, and besigliptin, but not saxagliptin), the conversion of nitrile group into carboxylic acid is their major metabolic pathway in vivo. DPP-4 was reported to be partly involved in the metabolism. In our pilot study, it was also observed that saxagliptin, a DPP-4 specific inhibitor, decreased the plasma exposures of besigliptin carboxylic acid in rats by only 20%. Therefore, it is speculated that some other enzymes may participate in nitrile group hydrolysis. After incubating gliptins with the cytosol, microsomes, and mitochondria of liver and kidney, carboxylic acid metabolites could all be formed. In recombinant DPP family such as DPP-4, DPP-2, DPP-8, DPP-9, and fibroblast activation protein-alpha, more hydrolytic metabolites were found. Among them, DPP-2 had the highest hydrolytic capacity besides DPP-4, and the DPP-4 inhibitor saxagliptin and DPP-2 inhibitor AX8819 can both inhibit the hydrolysis of gliptins. Western blot results showed that DPP-2 and DPP-4 existed in the aforementioned subcellular organelles at varying amounts. In rats, AX8819 decreased the plasma exposures of besigliptin carboxylic acid by 40%. The amide intermediates of gliptins were detected in vivo and in vitro. When the amide derivatives of gliptins were incubated with DPP-4, they were completely hydrolyzed at a rate far more than that from the parent drug, including saxagliptin-amide. Therefore, it was proposed that gliptins, except saxagliptin, were initially hydrolyzed to their amides by DPPs, which was the rate-limiting step in generating the carboxylic end product.
收录类别	SCI ; SCIE
语种	英语
资助项目	Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12050306]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Pharmacology & Pharmacy
WOS记录号	WOS:000457847500009
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS关键词	SAXAGLIPTIN ; IV ; VILDAGLIPTIN ; DISPOSITION ; EXPRESSION ; PROFILE ; POTENT
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/30248
专题	生命科学与技术学院_硕士生
通讯作者	Chen, Xiaoyan
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Kong, Fandi,Pang, Xiaoyan,Zhao, Jihui,et al. Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases[J]. DRUG METABOLISM AND DISPOSITION,2019,47(3):238-248.
APA	Kong, Fandi.,Pang, Xiaoyan.,Zhao, Jihui.,Deng, Pan.,Zheng, Mingyue.,...&Chen, Xiaoyan.(2019).Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases.DRUG METABOLISM AND DISPOSITION,47(3),238-248.
MLA	Kong, Fandi,et al."Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases".DRUG METABOLISM AND DISPOSITION 47.3(2019):238-248.