Received for publication September 28, 2006.
Revised December 13, 2006.
Accepted for publication December 15, 2006.

DISPOSITION OF THE DIPEPTIDYL PEPTIDASE-4 INHIBITOR SITAGLIPTIN IN RATS AND DOGS

Abstract

The pharmacokinetics, metabolism and excretion of sitagliptin (MK-0431), a potent dipeptidyl peptidase 4 inhibitor, were evaluated in male Sprague-Dawley rats and beagle dogs. The plasma clearance and volume of distribution of sitagliptin were higher in rats 40-48 mL/min/kg, 7-9 L/kg) than dogs (~9 mL/min/kg, ~3 L/kg), and its half-life was shorter in rats, ~2 hr compared to ~4 hr in dogs. Sitagliptin was absorbed rapidly after oral administration of a solution of the phosphate salt. The absolute oral bioavailability was high, and the pharmacokinetics were fairly dose-proportional. Following administration of [¹⁴C]sitagliptin, parent drug was the major radioactive component in rat and dog plasma, urine, bile and feces. Sitagliptin was eliminated primarily by renal excretion of parent drug; biliary excretion was an important pathway in rats, while metabolism was minimal in both species in vitro and in vivo. Approximately 10 to 16% of the radiolabeled dose was recovered in the rat and dog excreta as Phase I and II metabolites, which were formed by N-sulfation, N-carbamoyl glucuronidation, hydroxylation of the triazolopiperazine ring, and by oxidative desaturation of the piperazine ring followed by cyclization via the primary amine. The renal clearance of unbound drug in rats, 32-39 ml/min/kg, far exceeded the glomerular filtration rate, indicative of active renal elimination of parent drug.

Key words: bioavailability, drug absorption, drug clearance, drug disposition, drug secretion, mass spectrometry, metabolite identification, sulfate conjugation

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