The Absolute Oral Bioavailability and??Population-Based Pharmacokinetic Modelling of a Novel Dipeptidylpeptidase-IV Inhibitor, Vildagliptin, in Healthy Volunteers

Abstract

Vildagliptin is rapidly and well absorbed with an estimated absolute bioavailability of 85%. Two possible sites of absorption were identified, and the absorption rates were slower than the elimination rate, indicating a flip-flop phenomenon after oral dosing.

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

“…Given negligible protein binding (9.3% for vildagliptin and no binding for M20.7), the renal clearance was estimated to be 14.6 and 15.0 l/h for vildagliptin and M20.7, respectively, using the ratio of the total amount in urine (22.6 mg for vildagliptin and 49.6 mg for M20.7) relative to total AUC in plasma (1550 ng ⅐ h/ml for vildagliptin and 3350 ng ⅐ h/ml for M20.7). Similar renal clearances of vildagliptin (13.4 l/h) have also been reported after an intravenous dose (He et al, 2007a). With the protein binding correction (fu ϭ 90.7% for vildagliptin and 100% for M20.7), the unbound renal clearance of vildagliptin and M20.7 was estimated to be 16 and 15 l/h, respectively.…”

“…The CL/F and V z /F values of vildagliptin were 65.2 l/h and 269 liters, respectively. With a human bioavailability of 84%, the estimated CL was 55 l/h, which is slightly higher than that after an intravenous infusion dose (41 l/h) (He et al, 2007a). A measured V z value has not been reported in the literature, but V z can be estimated to be 229 liters based on data from this study.…”

“…This result is in agreement with the high absolute oral bioavailability of vildagliptin determined in healthy volunteers (85%) based on the single i.v. 25-mg dose (He et al, 2007a), suggesting a low first-pass metabolism and high intestinal absorption.…”

“…Vildagliptin has shown the ability to inhibit DPP-4, increase plasma concentrations of intact GLP-1 and glucose-dependent insulinotropic peptide, decrease fasting and postprandial glucose, and suppress plasma glucagons in clinical trial in patients with type 2 diabetes. The pharmacokinetics and pharmacodynamics of vildagliptin after various dosing regimens in healthy volunteers and patients with type 2 diabetes have been previously reported (He et al, 2007a(He et al, ,b, 2008Sunkara et al, 2007).…”

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

“…[13][14][15] Similarly long term treatment of voglibose induces enteroendocrine cells which have potential contribution to the enhancing effect on plasma active GLP-1 contents in gastrointestinal tracts secreted during meal, so that endogenous GLP1 activity is unexpectedly found to be ~1.6 fold increase in the lower intestine and ~1.4 -1.6 fold increase in colon. The increased active GLP-1 level in the colon has significant correlation with ~ 1.4 fold increase in gut gene expression levels of neurod 1 and ~2.6-3.1 fold increase in glucagon, thereby increases the release of the glucoregulatory hormone glucagon like peptide-1 (GLP-1) into the circulation which contribute to their glucose lowering effect, may have boosting effect on the gliptins.…”