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药品详细

Sitagliptin(西他列汀)

化学结构式图
中文名
西他列汀
英文名
Sitagliptin
分子式
C16H15F6N5O
化学名
(3R)-3-amino-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
分子量
Average: 407.3136
Monoisotopic: 407.118079357
CAS号
486460-32-6
ATC分类
A10B Oral Blood Glucose Lowering Drugs, Excl. Insulins
药物类型
small molecule
阶段
approved
商品名
Januvia;Januvia (Merck & Co.);Xelevia;
同义名
MK-0431;Sitagliptan;sitagliptin;Sitagliptin phosphate;
基本介绍

Sitagliptin is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. This enzyme-inhibiting drug is to be used either alone or in combination with metformin or a thiazolidinedione for control of type 2 diabetes mellitus. The drug works to competitively inhibit a protein/enzyme, dipeptidyl peptidase 4 (DPP-4), that results in an increased amount of active incretins (GLP-1 and GIP), reduced amount of release of glucagon (diminishes its release) and increased release of insulin.

生产厂家
  • Merck co inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA: Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 Dec;78(6):675-88. Pubmed
  2. Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan AG, Lasseter K, Dilzer S, Blum R, Wagner JA: Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. J Clin Pharmacol. 2006 Aug;46(8):876-86. Pubmed
  3. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP: Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008 Feb;24(2):489-96. Pubmed
  4. Pratley RE, Salsali A: Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin. 2007 Apr;23(4):919-31. Pubmed
  5. Bergman A, Ebel D, Liu F, Stone J, Wang A, Zeng W, Chen L, Dilzer S, Lasseter K, Herman G, Wagner J, Krishna R: Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers. Biopharm Drug Dispos. 2007 Sep;28(6):315-22. Pubmed
  6. Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C: Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health Risk Manag. 2008;4(4):753-68. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Triazolopyrazines
  • Phenethylamines
  • Amphetamines
Substructures
  • Amino Ketones
  • Triazoles
  • Aliphatic and Aryl Amines
  • Benzene and Derivatives
  • Triazolopyrazines
  • Halobenzenes
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Imines
  • Cyanamides
  • Aryl Halides
  • Amphetamines
适应症
Diabetes 糖尿病;
药理
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.
Pharmacodynamics Sitagliptin is an orally-active member of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. The benefit of this medicine is expected to be its lower side-effects of hypoglycemia in the control of blood glucose values. The drug works to diminish the effects of a protein/enzyme (by the inhibition of this protein/enzyme) on the pancreas at the level of release of glucagon (diminishes its release) and at the level of insulin (increases its synthesis and release) until blood glucose levels are restored toward normal, in which case the protein/enzyme-enzyme inhibitor becomes less effective and the amounts of insulin released diminishes thus diminishing the "overshoot" of hypoglycemia seen in other oral hypoglycemic agents.
Mechanism of action 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.
Absorption Rapidly absorbed following oral administration, with an absolute bioavailability of 87%.
Volume of distribution
  • 198 L [healthy subjects]
Protein binding The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metabolism
Sitagliptin does not undergo extensive metabolism. In vitro studies indicate that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4 (oxidation), with contribution from CYP2C8.
Route of elimination 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.
Half life 12.4 hours
Clearance
  • renal cl=350 mL/min [Healthy subjects receiving 100 mg oral dose]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
logP 1.5 Not Available
Predicted Properties
Property Value Source
water solubility 3.40e-02 g/l ALOGPS
logP 1.95 ALOGPS
logP 1.26 ChemAxon
logS -4.1 ALOGPS
pKa (strongest basic) 8.78 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 77.04 ChemAxon
rotatable bond count 5 ChemAxon
refractivity 87.49 ChemAxon
polarizability 32.66 ChemAxon
药物相互作用
Drug Interaction
Somatropin recombinant Somatropin may antagonize the hypoglycemic effect of sitagliptin. Monitor for changes in fasting and postprandial blood sugars.
食物相互作用
  • Can be administered without regard to food

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