Pharmacokinetics and metabolism of [¹⁴C]anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in humans

Abstract

1. The disposition of anagliptin, an orally active, highly selective dipeptidyl peptidase-4 inhibitor, was investigated after a single oral dose of 100 mg/1.92 MBq [(14)C]anagliptin to six healthy men. Almost all the dose (98.2%) was recovered within 168 h: 73.2% in urine and 25.0% in faeces. 2. Anagliptin was rapidly absorbed, with peak plasma concentrations of unchanged drug attained at a mean time of 1.8-h postdose. Mean fraction of the dose absorbed was >73%. Unchanged drug and a carboxylate metabolite (M1) were the major components in plasma, accounting for 66.0 and 23.4% of total plasma radioactivity area under the curve, respectively. 3. Anagliptin was incompletely metabolized, with about 50% dose eliminated as unchanged drug (46.6% in urine and 4.1% in faeces). Metabolism to M1 accounted for 29.2% of the dose. No other metabolite accounted for >1% dose in excreta or yielded measurable systemic exposure. Terminal half-life of anagliptin and M1 was 4.37 and 9.88 h, respectively. Renal clearance of unbound anagliptin and unbound M1 far exceeded glomerular filtration rate, indicating active renal elimination: that might reflect the fact that anagliptin may be a substrate of OAT1, OAT3, MDR1 and MRP2, and M1 a substrate of OAT3, BCRP, MRP2 and MRP4.

Dipeptidyl Peptidase-4 Greatly Contributes to the Hydrolysis of Vildagliptin in Human Liver

“…We also assessed inhibitory effect of BNPP (a carboxylesterase inhibitor) and ethopropazine (a butyrylcholinesterase inhibitor) on vildagliptin-hydrolyzing activity of human liver S9 fractions, because it has been reported that anagliptin, which has the same cyanopyrrolidine motif as vildagliptin, is metabolism by DPP-4, carboxylesterase, and butyrylcholinesterase (Furuta et al, 2013). However, the formation of M20.7 in human liver S9 fraction was not inhibited by BNPP and ethopropazine (Fig.…”

Comparative review of dipeptidyl peptidase‐4 inhibitors and sulphonylureas

“…Some have intrinsically long-half-lives (alogliptin, evogliptin, gemigliptin, linagliptin, omarigliptin, sitagliptin, teneligliptin and trelagliptin) [34][35][36][37][38][39], giving sustained DPP-4 inhibition which allows once-daily or, for omarigliptin and trelagliptin, once-weekly dosing. Others have much shorter half-lives (anagliptin, saxagliptin and vildagliptin) [34,40]; however, whereas the aforementioned inhibitors interact non-covalently with the enzyme, the cyanopyrrolide moiety in anagliptin, saxagliptin and vildagliptin promotes covalent binding, resulting in these inhibitors remaining bound to the enzyme for longer than predicted from their short half-lives [41,42]. Subsequent hydrolysis breaks the covalent bonds, releasing the drug, and these inhibitors are therefore sometimes described Alogliptin [34] >14 000 >14 000 >14 000 >14 000 >14 000 Anagliptin [19] n.r.…”

Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions

“…These interactions did not lead to covalent binding with the Og of Ser630, but could have resulted in a transition state in the formation of the covalent imidated intermediate. Based on the study of 14 C-labelled anagliptin, the major metabolite of anagliptin is known to be a hydrolysis product of the cyano group 28 . The metabolic mechanism of anagliptin therefore likely proceeds through the S 1 subsite via an imidate intermediate.…”