Molecule

Description

Sitagliptin phosphate (MK-0431) is a potent inhibitor of DPP-IV with IC50 of 19 nM in Caco-2 cell extracts.

Targets

IC₅₀

In Vitro

As an orally active agent, Sitagliptin phosphate exhibits a potent inhibitory effect on DPP-4 with IC50 of 19 nM from Caco-2 cell extracts. ^[1] MK0431 reduces in vitro migration of isolated splenic CD4 T-cells through a pathway involving cAMP/PKA/Rac1 activation. ^[2] A recent study demonstrates that sitagliptin exerts a novel, direct action in order to stimulate GLP-1 secretion by the intestinal L cell through a DPP-4-independent, protein kinase A- and MEK-ERK1/2-dependent pathway. It therefore reduces the effect of autoimmunity on graft survival. ^[3]

In Vivo

In vivo, the ED50 value of Sitagliptin phosphate for inhibition of plasma DPP-4 activity is calculated to be 2.3 mg/kg 7 hour postdose and 30 mg/kg 24 hour postdose in freely fed Han-Wistar rats. ^[1] The streptozotocin-induced type 1 diabetes mouse model exhibits elevated DPP-4 levels in the plasma that can be substantially inhibited in mice on an Sitagliptin phosphate diet. This is achieved by a positive effect on the regulation of hyperglycemia, potentially through prolongation of islet graft survival. ^[4] The plasma clearance and volume of distribution of Sitagliptin phosphate are higher in rats (40–48 mL/min/kg, 7–9 L/kg) than in dogs (9 mL/min/kg, 3 L/kg); and its half-life is shorter in rats,2 hours compared with 4 hours in dogs. ^[5]

Clinical Trials

Sitagliptin phosphate is currently under Phase III clinical trials in patients with type 2 diabetes.

Features

Sitagliptin phosphate is a potent, orally active inhibitor of DPP-4.

Cell Lines

CD4 T-cells

Concentrations

100 μM

Incubation Time

1 hour

Methods

CD4T-cells are plated on membrane inserts in serum-free RPMI 1640, and cell migration is assayed using Transwell chambers (Corning), in the presence or absence of purified porcine kidney DPP-4 (32.1 units/mg; 100 mU/mL final concentration) and DPP-4 inhibitor (100 μM). After 1 hour, cells on the upper surface are removed mechanically, and cells that have migrated into the lower compartment are counted. The extent of migration is expressed relative to the control sample.

Animal Models

Freely fed Han-Wistar rats

Formulation

0.5% aqueous hyroxyethylcellulose.

Doses

≤10 mg/kg

Administration

Administered via p.o.