Pharmacokinetics and metabolism of [14C]anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in humans.
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.
Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho, Co. Ltd, Mie, Japan. s_furuta@mb4.skk-net.com
Shinji
S
Furuta
Clair
C
Smart
Andrew
A
Hackett
Rajdeep
R
Benning
Steve
S
Warrington
D000328:Adult; D002250:Carbon Radioisotopes / Q000097:blood / Q000493:pharmacokinetics; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D002250:Carbon Radioisotopes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011743:Pyrimidines; C583175:anagliptin