RT Journal Article
SR Electronic
T1 Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 238
OP 248
DO 10.1124/dmd.118.084640
VO 47
IS 3
A1 Fandi Kong
A1 Xiaoyan Pang
A1 Jihui Zhao
A1 Pan Deng
A1 Mingyue Zheng
A1 Dafang Zhong
A1 Xiaoyan Chen
YR 2019
UL http://dmd.aspetjournals.org/content/47/3/238.abstract
AB 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-α, 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.