Sitagliptin

spinqualitylabelsall models Sitagliptin, better known as Januvia, (1x70) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Better Known as: Januvia

• Marketed By: Merck & Co.
• Major Indication: Hyperglycemia & Type II Diabetes
• Drug Class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor
• Date of FDA Approval (Patent Expiration): 2006 (2017)
• 2009 Sales: $2.4 Billion
• Importance: One of the best selling treatments for Type II Diabetes. Often used in combination with Metformin, the first line anti-diabetic medication (Combination sold as Janumet). Has an excellent side-effect profile with a relatively low incidence of hypoglycemia an weight gain. Increasing evidence that all DPP-4 inhibitors can to certain malignant cancers.
• See Pharmaceutical Drugs for more information about other drugs and diseases.

Mechanism of Action

Type II Diabetes is a chronic metabolic disorder caused by pancrease β-cell dysfunction, deficiency in insulin secretion or insulin resistance, and/or increased hepatic glucose production. Numerous complex systems are involved in this disorder, with several protein serving as therapeutic targets. Dipeptidyl Peptidase-4 (DPP-4) is an antigenic membrane serine exopeptidase that cleaves proline dipeptides form the N-terminal end of protein substrates. DPP-4 plays a major role in glucose metabolism as it is responsible for the degradation of incretins, most notably Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIp). Incretins are a group of gastrointestinal hormones that stimulate insulin biosynthesis and inhibit glucagon secretion after consuming high glucose meals. Sitagliptin is a competitive inhibitor of DPP-4. By inhibiting DPP-4 and subsequently preventing the enzymatic degradation of GLP-1 and GIP, these incretins are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. The result is controlled blood-glucose levels, a major concern for diabetics.

Pharmacokinetics

DPP4 Inhibitor Pharmacokinetics Parameter Vildagliptin (Galvus) Sitagliptin (Januvia) Saxagliptin (Onglyza) Tmax (hr) 1.75 1-4 2 Cmax (ng/ml) 290 330 34 Bioavailability (%) 85 87 67 Protein Binding (%) 9 38 0 T1/2 (hr) 2-3 12.4 2.5 AUC (ng/ml/hr) 1610 3470 101 IC50 (nM) 3 18 50 Renal Clearance (L/h) 13.0 21.0 13.8 Volume Distribution (L) 71 198 151 Dosage (mg) 100 100 5 Metabolism Hydrolysis Hepatic (CYP3A4 & CYP2C8) Hepatic (CYP3A4) For Pharmacokinetic Data References, see: References