RT Journal Article
SR Electronic
T1 Disposition of Vildagliptin, a Novel Dipeptidyl Peptidase 4 Inhibitor, in Rats and Dogs
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 545
OP 554
DO 10.1124/dmd.108.023002
VO 37
IS 3
A1 Handan He
A1 Phi Tran
A1 Hequn Yin
A1 Harold Smith
A1 Dennis Flood
A1 Roger Kramp
A1 Ron Filipeck
A1 Volker Fischer
A1 Dan Howard
YR 2009
UL http://dmd.aspetjournals.org/content/37/3/545.abstract
AB The pharmacokinetics, absorption, metabolism, and excretion of vildagliptin, a potent and orally active inhibitor of dipeptidyl peptidase 4, were evaluated in male rats and dogs. Vildagliptin was rapidly absorbed with peak plasma concentrations occurring between 0.5 and 1.5 h. Moderate to high bioavailability was observed in both species (45–100%). The distribution and elimination half-lives of vildagliptin were short: 0.57 h [82% of area under the plasma drug concentration-time curve (AUC)] and 8.8 h in the rat and 0.05 and 0.89 h (87% of AUC) in the dog, respectively. The volume of distribution was 1.6 and 8.6 l/kg in dogs and rats, respectively, indicating moderate to high tissue distribution. The plasma clearance of vildagliptin was relatively high for the rat (2.9 l/h/kg) and dog (1.3 l/h/kg) compared with their hepatic blood flow. The major circulating components in plasma after an intravenous or oral dose were the parent compound (rat and dog), a carboxylic acid metabolite from the hydrolysis of the amide bond M15.3 (dog), and a carboxylic acid metabolite from the hydrolysis of the cyano moiety M20.7 (rat and dog). After intravenous dosing, urinary excretion of radioactivity (47.6–72.4%) was the major route of elimination for rats and dogs as 18.9 to 21.3% of the dose was excreted into urine as unchanged parent drug. The recovery was good in both species (81–100% of the dose). Vildagliptin was mainly metabolized before excretion in both species. Similar to plasma, the most predominant metabolite in excreta was M20.7 in rats and dogs, and another major metabolite in dogs was M15.3. The American Society for Pharmacology and Experimental Therapeutics