Pharmacokinetic disposition of anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in rats and dogs

Abstract

The pharmacokinetic disposition of anagliptin, an orally active and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated in male rats and dogs. Anagliptin was well absorbed in dogs (70.4%) and moderately to well absorbed in rats ranging from 38.1 to 85.5% depending on the dose. In situ testing indicated that anagliptin absorption from rat intestine was apparently limited by P-glycoprotein. The absorbed radioactivity was distributed rapidly throughout the body, and high levels of radioactivity were found in the tissues expressing DPP-4 at high levels, especially small intestine, kidney and liver. In both species, the major circulating component was unchanged anagliptin; major circulating metabolites were M1 resulting from hydrolysis of the cyano group and M6 and M7, both of which resulting from the oxidation-cleavage of the methylene function adjacent to the amine. After intravenous dosing, urinary excretion of radioactivity was the major route of elimination for rats (64.6%) and dogs (66.2%), and biliary excretion was demonstrated to be an important pathway in rats (25.2%). The total recovery was good (97.5-99.5%) and most of the radioactivity was excreted by 24h in both species. The renal clearance of unbound anagliptin in rats (91.7ml/min/kg) was much higher than the glomerular filtration rate, indicative of active renal elimination.