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药品详细

Saxagliptin(沙格列汀)

化学结构式图
中文名
沙格列汀
英文名
Saxagliptin
分子式
C18H25N3O2
化学名
(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile
分子量
Average: 315.41
Monoisotopic: 315.194677059
CAS号
361442-04-8
ATC分类
A10B Oral Blood Glucose Lowering Drugs, Excl. Insulins
药物类型
small molecule
阶段
approved
商品名
Onglyza (Bristol-Myers Squibb);
同义名
BMS-477118;Onglyza;saxagliptin;
基本介绍

Saxagliptin (rINN) is an orally active hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. FDA approved on July 31, 2009.

生产厂家
  • Bristol myers squibb co
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Rosenstock J, Sankoh S, List JF: Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab. 2008 May;10(5):376-86. Epub 2008 Mar 18. Pubmed
  2. Metzler WJ, Yanchunas J, Weigelt C, Kish K, Klei HE, Xie D, Zhang Y, Corbett M, Tamura JK, He B, Hamann LG, Kirby MS, Marcinkeviciene J: Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation. Protein Sci. 2008 Feb;17(2):240-50. Pubmed
  3. Crepaldi G, Carruba M, Comaschi M, Del Prato S, Frajese G, Paolisso G: Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in Type 2 diabetes management. J Endocrinol Invest. 2007 Jul-Aug;30(7):610-4. Pubmed
  4. 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. Pubmed# Kulasa K, Edelman S: Saxagliptin: the evidence for its place in the treatment of type 2 diabetes mellitus. Core Evid. 2010 Oct 21;5:23-37. Pubmed
  5. Russell S: Incretin-based therapies for type 2 diabetes mellitus: a review of direct comparisons of efficacy, safety and patient satisfaction. Int J Clin Pharm. 2013 Apr;35(2):159-72. doi: 10.1007/s11096-012-9729-9. Epub 2012 Dec 22. Pubmed
  6. Ali S, Fonseca V: Saxagliptin overview: special focus on safety and adverse effects. Expert Opin Drug Saf. 2013 Jan;12(1):103-9. doi: 10.1517/14740338.2013.741584. Epub 2012 Nov 9. Pubmed
  7. Golightly LK, Drayna CC, McDermott MT: Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet. 2012 Aug 1;51(8):501-14. doi: 10.2165/11632930-000000000-00000. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes Not Available
Substructures Not Available
适应症
Diabetes 糖尿病;
药理
Indication Treatment of type 2 diabetes mellitus to improve glycemic control in combination with other agents or as monotherapy.
Pharmacodynamics Post-administration of saxagliptin, GLP-1 and GIP levels rise up to 2- to 3- fold. Because it is very selective of DPP-4 inhibition, there are fewer systemic side effects. Saxagliptin inhibits DPP-4 enzyme activity for a 24-hour period. It also decreased glucagon concentrations and increased glucose-dependent insulin secretion from pancreatic beta cells. The half maximal inhibitory concentration (IC50) is 0.5 nmol/L. Saxagliptin did not prolong the QTc interval to a clinically significant degree.
Mechanism of action Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor antidiabetic for the treatment of type 2 diabetes. DPP-4 inhibitors are a class of compounds that work by affecting the action of natural hormones in the body called incretins. Incretins decrease blood sugar by increasing consumption of sugar by the body, mainly through increasing insulin production in the pancreas, and by reducing production of sugar by the liver. [Bristol-Myers Squibb Press Release] DPP-4 is a membrane associated peptidase which is found in many tissues, lymphocytes and plasma. DPP-4 has two main mechanisms of action, an enzymatic function and another mechanism where DPP-4 binds adenosine deaminase, which conveys intracellular signals via dimerization when activated. Saxagliptin forms a reversible, histidine-assisted covalent bond between its nitrile group and the S630 hydroxyl oxygen on DPP-4. The inhibition of DPP-4 increases levels active of glucagon like peptide 1 (GLP-1), which inhibits glucagon production from pancreatic alpha cells and increases production of insulin from pancreatic beta cells.
Absorption Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. Saxagliptin did not accumulate following repeated doses. The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Bioavailability, 2.5 - 50 mg dose = 67%
Volume of distribution

151 L
Protein binding The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible (<10%).
Metabolism
The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). 50% of the absorbed dose will undergo hepatic metabolism. The major metabolite of saxagliptin, 5-hydroxy saxagliptin, is also a DPP4 inhibitor, which is one-half as potent as saxagliptin.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Saxagliptin
5-hydroxy saxagliptin Details
Route of elimination Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract.
Half life Saxagliptin = 2.5 hours; 5-hydroxy saxagliptin = 3.1 hours;
Clearance

Renal clearance, single 50 mg dose = 14 L/h
Toxicity Adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with placebo are: upper respiratory tract infection, urinary tract infection, and headache.
Affected organisms Not Available
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
water solubility Sparingly soluble FDA label
Predicted Properties
Property Value Source
water solubility 2.26e+00 g/l ALOGPS
logP 0.88 ALOGPS
logP -0.08 ChemAxon
logS -2.1 ALOGPS
pKa (strongest acidic) 14.74 ChemAxon
pKa (strongest basic) 7.9 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 90.35 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 83.99 ChemAxon
polarizability 34.22 ChemAxon
药物相互作用
Drug Interaction
Clarithromycin Clarithromycin is an inhibitor of CYP3A4 which increases exposure of saxagliptin. Decrease dose of saxagliptin to 2.5 mg per day.
Conivaptan CYP3A4 Inhibitors (Strong) may increase the serum concentration of Saxagliptin. Limit saxagliptin dose to 2.5 mg/day and monitor for increased saxagliptin levels/effects (e.g., hypoglycemia) with concomitant administration of a strong CYP3A4 inhibitor (e.g., ketoconazole). Monitor for decreased saxagliptin levels/effects with discontinuation of concomitant CYP3A4 inhibitor.
Diltiazem Diltiazem is a moderate inhibitor of CYP3A4 and increases AUC of saxagliptin by 109%. Exposure of the active metabolite decreased by 34%. However, these changes in pharmacokinetics are not clinical significant.
Erythromycin Erythromycin is an inhibitor of CYP3A4 which increases exposure of saxagliptin. Decrease dose of saxagliptin to 2.5 mg per day.
Indinavir Indinavir is an inhibitor of CYP3A4 which increases exposure of saxagliptin. Decrease dose of saxagliptin to 2.5 mg per day.
Ketoconazole Ketoconazole is a strong inhibitor of CYP3A4/5 which increases exposure of saxagliptin. The exposure of the active metabolite, 5-hydroxy saxagliptin, also decreases. Decrease dose of saxagliptin to 2.5 mg per day.
Nefazodone Nefazodone is an inhibitor of CYP3A4 which increases exposure of saxagliptin. Decrease dose of saxagliptin to 2.5 mg per day.
Nelfinavir Nelfinavir is an inhibitor of CYP3A4 which increases exposure of saxagliptin. Decrease dose of saxagliptin to 2.5 mg per day.
Rifampin Rifampin is a strong inducer of CYP3A4 which decreases exposure of saxagliptin. The exposure of the active metabolite, 5-hydroxy saxagliptin, also increases.
Ritonavir Ritonavir is an inhibitor of CYP3A4 which increases exposure of saxagliptin. Decrease dose of saxagliptin to 2.5 mg per day.
Simvastatin Simvastatin is a moderate inhibitor of CYP3A4 and increases AUC of saxagliptin by 12%. Exposure of the active metabolite decreased by 2%. However, these changes in pharmacokinetics are not clinical significant.
Somatropin recombinant Somatropin may antagonize the hypoglycemic effect of saxagliptin. Monitor for changes in fasting and postprandial blood sugars.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of saxagliptin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of saxagliptin if voriconazole is initiated, discontinued or dose changed.
食物相互作用
  • Administration with a high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions.

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