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

Abstract

ABSTRACT:The absorption, metabolism, and excretion of (1-[[3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine (vildagliptin), an orally active and highly selective dipeptidyl peptidase 4 inhibitor developed for the treatment of type 2 diabetes, were evaluated in four healthy male subjects after a single p.o. 100-mg dose of [ 14 C]vildagliptin. Serial blood and complete urine and feces were collected for 168 h postdose. Vildagliptin was rapidly absorbed, and peak plasma concentrations were attained at 1.1 h postdose. The fraction of drug absorbed was calculated to be at least 85.4%. Unchanged drug and a carboxylic acid metabolite (M20.7) were the major circulating components in plasma, accounting for 25.7% (vildagliptin) and 55% (M20.7) of total plasma radioactivity area under the curve. The terminal half-life of vildagliptin was 2.8 h. Complete recovery of the dose was achieved within 7 days, with 85.4% recovered in urine (22.6% unchanged drug) and the remainder in feces (4.54% unchanged drug). Vildagliptin was extensively metabolized via at least four pathways before excretion, with the major metabolite M20.7 resulting from cyano group hydrolysis, which is not mediated by cytochrome P450 (P450) enzymes. Minor metabolites resulted from amide bond hydrolysis (M15.3), glucuronidation (M20.2), or oxidation on the pyrrolidine moiety of vildagliptin (M20.9 and M21.6). The diverse metabolic pathways combined with a lack of significant P450 metabolism (1.6% of the dose) make vildagliptin less susceptible to potential pharmacokinetic interactions with comedications of P450 inhibitors/inducers. Furthermore, as vildagliptin is not a P450 inhibitor, it is unlikely that vildagliptin would affect the metabolic clearance of comedications metabolized by P450 enzymes.

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

“…In addition, the metabolism in DPP-4-deficient rats to elucidate the hydrolysis mechanism is discussed. The absorption, metabolism, and excretion of vildagliptin in humans are reported in the accompanying article (He et al, 2009). …”

Effect of co-administration of voglibose and vildagliptin on diabetic albino rats

“…They have shown that co-administration of vildagliptin and voglibose have synergistic effect on achieving adequate glycemic control. 6 Potential antihyperglycemic effect together with achievement of glycemic target just in 7-21 days confirms their efficacy comparable to traditional antidiabetic agent. Maintenance of euglycemia throughout study not only proves their effectiveness but may also suggest beta cell (both mass and function) preserving role and their insulinotropic activity in diabetes mellitus.…”

“…Yamaguchi M, Saji T, Mita S et al also found that the most remarkable advantage of their co-administration was to increase beta cell mass and function. 6 Vildagliptin, a dipeptidyl peptidase-1(DPP-4) inhibitor, decreases the inactivation of glucagon like peptide-1 (GLP-1) thereby increasing its secretion, accompanied with a decrease in that of glucagon.…”

“…5 Better efficacy and tolerability was found when it was given for long period and helped in alleviating undesired consequences and progression of diabetic complications. 6 Supported literature regarding this are few; so this study was done to compare the antihyperglycemic effect of voglibose and vildagliptin in co-administration with each individual drug alone.…”

A Validated Reversed-Phase HPLC Method for the Determination of Vildagliptin from Tablet Dosage Form

“…Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP IV, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas . [1][2][3][4][5] …”