Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases
文献类型：期刊论文
| 作者 | Kong, Fandi3; Pang, Xiaoyan3; Zhao, Jihui1; Deng, Pan2; Zheng, Mingyue3 ; Zhong, Dafang3; Chen, Xiaoyan3
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| 刊名 | Drug metabolism and disposition: the biological fate of chemicals
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| 出版日期 | 2018-12-10 |
| ISSN号 | 1521-009X |
| DOI | 10.1124/dmd.118.084640 |
| 文献子类 | Article |
| 英文摘要 | 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, 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-α, more hydrolytic metabolites were found. Among them, DPP-2 had the highest hydrolytic capacity besides DPP-4. And 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 above 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. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/266246]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Chen, Xiaoyan |
| 作者单位 | 1.ShanghaiTech University; 2.Shanghai Institute of Materia Medica, Chinese Academy of Sciences 3.Shanghai Institute of Materia Medica; |
| 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: the biological fate of chemicals,2018. |
| APA | Kong, Fandi.,Pang, Xiaoyan.,Zhao, Jihui.,Deng, Pan.,Zheng, Mingyue.,...&Chen, Xiaoyan.(2018).Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases.Drug metabolism and disposition: the biological fate of chemicals. |
| MLA | Kong, Fandi,et al."Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases".Drug metabolism and disposition: the biological fate of chemicals (2018). |
入库方式： OAI收割
来源：上海药物研究所
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