PT - JOURNAL ARTICLE AU - Aberra Fura AU - Ashish Khanna AU - Viral Vyas AU - Barry Koplowitz AU - Shu-Ying Chang AU - Christian Caporuscio AU - David W. Boulton AU - Lisa J. Christopher AU - Kristina D. Chadwick AU - Lawrence G. Hamann AU - W. Griffith Humphreys AU - Mark Kirby TI - Pharmacokinetics of the Dipeptidyl Peptidase 4 Inhibitor Saxagliptin in Rats, Dogs, and Monkeys and Clinical Projections AID - 10.1124/dmd.108.026088 DP - 2009 Jun 01 TA - Drug Metabolism and Disposition PG - 1164--1171 VI - 37 IP - 6 4099 - http://dmd.aspetjournals.org/content/37/6/1164.short 4100 - http://dmd.aspetjournals.org/content/37/6/1164.full SO - Drug Metab Dispos2009 Jun 01; 37 AB - Saxagliptin is a potent, selective, reversible dipeptidyl peptidase 4 (DPP4) inhibitor specifically designed for extended inhibition of the DPP4 enzyme and is currently under development for the treatment of type-2 diabetes. The pharmacokinetics of saxagliptin were evaluated in rats, dogs, and monkeys and used to predict its human pharmacokinetics. Saxagliptin was rapidly absorbed and had good bioavailability (50–75%) in the species tested. The plasma clearance of saxagliptin was higher in rats (115 ml/min/kg) than in dogs (9.3 ml/min/kg) and monkeys (14.5 ml/min/kg) and was predicted to be low to moderate in humans. The plasma elimination half-life was between 2.1 and 4.4 h in rats, dogs, and monkeys, and both metabolism and renal excretion contributed to the overall elimination. The primary metabolic clearance pathway involved the formation of a significant circulating, pharmacologically active hydroxylated metabolite, M2. The volume of distribution values observed in rats, dogs, and monkeys (1.3–5.2 l/kg) and predicted for humans (2.7 l/kg) were greater than those for total body water, indicating extravascular distribution. The in vitro serum protein binding was low (≤30%) in rats, dogs, monkeys, and humans. After intra-arterial administration of saxagliptin to Sprague-Dawley and Zucker diabetic fatty rats, higher levels of saxagliptin and M2 were observed in the intestine (a proposed major site of drug action) relative to that in plasma. Saxagliptin has prolonged pharmacodynamic properties relative to its plasma pharmacokinetic profile, presumably due to additional contributions from M2, distribution of saxagliptin and M2 to the intestinal tissue, and prolonged dissociation of both saxagliptin and M2 from DPP4. The American Society for Pharmacology and Experimental Therapeutics