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Sitagliptin
- indication:For use as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Also for use in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a PPARγ agonist (e.g., thiazolidinediones) when the single agent alone, with diet and exercise, does not provide adequate glycemic control.
- pharmacologypharmacology:
- mechanism: Sitagliptin is a highly selective DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones, thereby increasing the concentration and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. These changes lead to a decrease in hemoglobin A1c (HbA1c)levels, as well as a lower fasting and postprandial glucose concentration. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
- toxicity:
- absorprion: Rapidly absorbed following oral administration, with an absolute bioavailability of 87%.
- halflife: 12.4 hours
- roouteelimination: Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination. Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
- volumedistribution: * 198 L [healthy subjects]
- clearance: * renal cl=350 mL/min [Healthy subjects receiving 100 mg oral dose]