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 [¹⁴C]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.

Keywords::

• Anagliptin
• DPP-4 inhibitor
• pharmacokinetics
• metabolism
• excretion
• human

Acknowledgements

A part of this work was performed in cooperation with Kowa Co. Ltd and Sekisui Medical Co. Ltd. The authors thank all the members of those companies for valuable suggestions regarding the analysis of the data.

Declaration of interest

The authors report no conflicts of interest, other than those that are obvious from their affiliations. The authors alone are responsible for the content and writing of the paper.