(Rac)-Sitagliptin is an isomer of Sitagliptin. Sitagliptin (MK-0431) is an effective, orally active DPP4 inhibitor with an IC50 value of 19 nM in Caco-2 cells.

Sitagliptin phosphate is a potent inhibitor of DPP-4, with an IC50 value of 19 nM in Caco-2 cell extracts. It reduces the in vitro migration of isolated splenic CD4 T cells via a cAMP/PKA/Rac1 activation pathway. Sitagliptin exerts a novel direct effect by stimulating GLP-1 secretion from intestinal L cells through a DPP-4-independent, protein kinase A and MEK-ERK1/2-dependent mechanism, and it may reduce the impact of autoimmunity on graft survival.

In vivo, sitagliptin phosphate demonstrates an ED50 of 2.3 mg/kg at 7 hours post-administration and 30 mg/kg at 24 hours in freely-fed Han-Wistar rats for inhibiting plasma DPP-4 activity. In a streptozotocin-induced type 1 diabetes mouse model, elevated plasma DPP-4 levels are significantly reduced upon administration of sitagliptin phosphate, likely enhancing graft survival through improved hyperglycemic regulation. The plasma clearance and volume of distribution of sitagliptin phosphate in rats (40-48 mL/min/kg, 7-9 L/kg) exceed those observed in dogs (9 mL/min/kg, 3 L/kg), with a shorter half-life in rats (2 hours) compared to dogs (4 hours) [5].