Sitagliptin

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Sitagliptin, better known as Januvia, (1x70)

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.[1]
  • See Pharmaceutical Drugs for more information about other drugs and diseases.

Mechanism of Action

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. Since Diabetes is typically caused by a deficiency in insulin secretion or by increased hepatic glucose production, preventing incretin degradation is a viable treatment for diabetics. Sitagliptin is a . 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, resulting in controlled blood-glucose levels.[2] The active site of DPP-4 consists of a and several , ideal for binding terminal dipeptides. with great specificity (DPP-4 IC50: 18 nM vs. >50,000 nM for other DPPs), situating its trifluorophenyl moiety within the S1 hydrophobic pocket, forming four hydrogen bond interactions with residues Tyr 662, Glu 205, & Glu 206, and burying its trifluoro group within a a very tight pocket formed by residues Ser 209 and Arg 358.[3]

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

References

  1. Wesley UV, McGroarty M, Homoyouni A. Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. Cancer Res. 2005 Feb 15;65(4):1325-34. PMID:15735018 doi:10.1158/0008-5472.CAN-04-1852
  2. Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract. 2006 Nov;60(11):1454-70. PMID:17073841 doi:10.1111/j.1742-1241.2006.01178.x
  3. Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H, Hickey GJ, Kowalchick JE, Leiting B, Lyons K, Marsilio F, McCann ME, Patel RA, Petrov A, Scapin G, Patel SB, Roy RS, Wu JK, Wyvratt MJ, Zhang BB, Zhu L, Thornberry NA, Weber AE. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin -7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005 Jan 13;48(1):141-51. PMID:15634008 doi:10.1021/jm0493156


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