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Biological Activity
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Description
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Sitagliptin phosphate (MK-0431) is a potent inhibitor of DPP-IV with IC50 of 19 nM in Caco-2 cell extracts. |
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Targets
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DPP-4 |
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IC50 |
19 nM [1] |
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In Vitro
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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] |
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In Vivo
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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] |
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Clinical Trials
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Sitagliptin phosphate is currently under Phase III clinical trials in patients with type 2 diabetes. |
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Features
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Sitagliptin phosphate is a potent, orally active inhibitor of DPP-4. |
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Protocol
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Cell Assay
[2]
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| 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. |
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Animal Study
[1]
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| Animal Models |
Freely fed Han-Wistar rats |
| Formulation |
0.5% aqueous hyroxyethylcellulose. |
| Doses |
≤10 mg/kg |
| Administration |
Administered via p.o. |
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