Reditn Mechanism of Action

Pharmacology: Pharmacodynamics: Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active, intact hormones are increased by sitagliptin, thereby increasing 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, and GLP-1 slows gastric emptying time. Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner; GLP-1 does not increase insulin secretion when the glucose concentration is less than 90 mg/dL. The contributions of GIP, which increases insulin secretion and regulates fat metabolism, overall effects of sitagliptin are unclear at this time. Sitagliptin is of benefit in patients with type 2 diabetes mellitus as their GLP-1 concentrations are decreased in response to a meal. 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. The long-term safety of DPP-4 inhibitors are currently under investigation as DPP-4 is not an enzyme specific for the breakdown of incretin hormones. In fact, DPP-4 is responsible for the metabolism of many peptides including peptide YY, neuropeptide Y, and growth hormone-releasing hormone. DPP-4 is involved with T-cell activation and is expressed on lymphocytes as CD26. Whether there are long-term neurological or immunological consequences of inhibiting DPP-4 is unclear at this time.
Pharmacokinetics: Absorption: Bioavailability: Absolute bioavailability of sitagliptin is 87%.
Rapidly absorbed following oral administration; at steady state (within 3 days of therapy initiation), peak plasma concentrations generally attained ≤3 hours following administration of recommended doses.
Onset: Reduction in postprandial plasma glucose excursion: Approximately 60 minutes.
Duration: Approximately 80% inhibition of DPP-4 activity persists for 12 or 24 hours following administration of ≥50 or ≥100 mg, respectively, of sitagliptin.
Food: Food does not appear to affect absorption.
Special Populations: Renal impairment results in increased plasma AUC. Removed modestly by hemodialysis; time to peak plasma drug concentration increased in a limited number of patients with end-stage renal disease requiring hemodialysis.
Moderate hepatic impairment results in increased peak plasma concentrations and AUC not considered clinically important.
In geriatric patients, modest increases in plasma concentrations compared with younger adults.
Distribution: Extent: Distributed into milk in rats not known whether distributed into human milk.
Plasma Protein Binding: 38%.
Metabolism: Metabolized to a limited extent by CYP isoenzymes 3A4 and 2C8 to inactive metabolites.
Elimination Route: Eliminated principally by kidneys via active tubular secretion. Excreted in urine (87%) mainly as unchanged drug and in feces (13%).
Half-life: 12.4 hours.
Special Populations: Renal impairment results in increased terminal elimination half-life.