Disposition of vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in rats and dogs.
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.
He
Handan
H
Department of Drug Metabolism, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA. handan.he@novartis.com
Tran
Phi
P
Yin
Hequn
H
Smith
Harold
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Flood
Dennis
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Kramp
Roger
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Filipeck
Ron
R
Fischer
Volker
V
Howard
Dan
D
D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics*; D004285:Dogs; D066298:In Vitro Techniques; D008297:Male; D009570:Nitriles / Q000493:pharmacokinetics*; D011485:Protein Binding; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D000077597:Vildagliptin
D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane