Disposition of Vildagliptin, a Novel Dipeptidyl Peptidase 4 Inhibitor, in Rats and Dogs

Abstract

ABSTRACT: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 halflives 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 administration of dipeptidyl peptidase IV (DPP-4) inhibitors to diabetics has been proven to augment endogenous glucagon-like peptide-1 (GLP-1) activity, which in turn produces a clinically significant lowering of diabetic glycemia comparable with that observed when GLP-1 is administered by direct infusion (Gutniak et al., 1992(Gutniak et al., , 1997Deacon et al., 1995;Mentlein, 1999;Drucker, 2003;Mest and Mentlein, 2005). Vildagliptin (Galvus, LAF237, 1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine) is a potent, orally active inhibitor of DPP-4, which has been shown to ameliorate hyperglycemia in diabetic patients by preventing the cleavage and inactivation of GLP-1. Vildagliptin is now commercially available in the European market (Villhauer et al., 2003;He et al., 2007).The IC 50 of vildagliptin against the DPP-4 enzyme is 2 nM, based on the in vitro recombinant DPP-4 assay, indicating high potency. In humans, the effect of vildagliptin on DPP-4 inhibition is reflected in an IC 50 of 4.5 nM, a value that suggests higher potency than that reported for another DPP-4 inhibitor, sitagliptin (IC 50 of 26 nM) (Herman et al., 2005;He et al., 2007). To aid in the selection of appropriate species for preclinical testing, the disposition of vildagliptin was evaluated in the rat and dog and compared with that in the human. Results from in vivo absorption, metabolism, and excretion studies in rat and dogs as wel...

Absorption, Metabolism, and Excretion of [14C]Vildagliptin, a Novel Dipeptidyl Peptidase 4 Inhibitor, in Humans

“…The elimination of vildagliptin in humans was comparable with that in rats and dogs, being primarily metabolized to M20.7 and excreted as unchanged drug (He et al, 2009). The other major pathway in dogs was the hydrolysis at the amide bond (M15.3).…”

“…However, M20.7 was observed in the human liver slice, confirming the hydrolysis occurs in liver, possibly in the cytosolic fraction. Furthermore, based on findings from the in vivo metabolism data in DPP-4-deficient rats (He et al, 2009), approximately 20% of the cyano group hydrolysis reaction (formation of main metabolite M20.7) may be attributable to the DPP-4 enzyme. Indeed, the formation of M20.7 was found to be catalyzed by human recombinant DDP-IV in vitro, supporting the contribution of this enzyme to this metabolic transformation.…”

“…14 C]Vildagliptin has been shown to be highly absorbed in both rats and dogs (He et al, 2009). Vildagliptin was mainly metabolized before excretion in rats and dogs.…”

Dipeptidyl Peptidase-4 Greatly Contributes to the Hydrolysis of Vildagliptin in Human Liver

“…In mice, rats, dogs, and humans, the main metabolite of vildagliptin is M20.7 (He et al, 2009b). In our previous study, we investigated whether human nitrilase-like protein (NIT)1 and NIT2, which are members of the nitrilase superfamily, are involved in the hydrolysis of vildagliptin, because the hydrolysis of the cyano group of vildagliptin is similar to nitrilase reaction (Asakura et al, 2014).…”

“…In contrast, non-CYP enzymes, such as uridine diphosphate glucuronosyltransferase and esterase, have attracted recent attention in pharmacokinetics, including metabolism and drug-drug interaction (Nagai, 2010;Akabane et al, 2012;Fukami and Yokoi, 2012). Identification of the major metabolic enzyme responsible for vildagliptin hydrolysis is important in predicting the individual differences in pharmacokinetics and is useful for the prediction of drug-drug interactions with vildagliptin via non-CYP.In mice, rats, dogs, and humans, the main metabolite of vildagliptin is M20.7 (He et al, 2009b). In our previous study, we investigated whether human nitrilase-like protein (NIT)1 and NIT2, which are members of the nitrilase superfamily, are involved in the hydrolysis of vildagliptin, because the hydrolysis of the cyano group of vildagliptin is similar to dx.doi.org/10.1124/dmd.114.062331.…”