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药品详细

Repaglinide(瑞格列奈)

化学结构式图
中文名
瑞格列奈
英文名
Repaglinide
分子式
C27H36N2O4
化学名
2-ethoxy-4-({[(1S)-3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl]carbamoyl}methyl)benzoic acid
分子量
Average: 452.5857
Monoisotopic: 452.26750765
CAS号
135062-02-1
ATC分类
A10B Oral Blood Glucose Lowering Drugs, Excl. Insulins
药物类型
small molecule
阶段
approved
商品名
Prandin;
同义名
AG-EE 388 ZW;AG-EE 623 ZW;Repaglinida [INN-Spanish];repaglinide;Repaglinidum [INN-Latin];
基本介绍

Repaglinide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It belongs to the meglitinide class of short-acting insulin secretagogues, which act by binding to β cells of the pancreas to stimulate insulin release. Repaglinide induces an early insulin response to meals decreasing postprandial blood glucose levels. It should only be taken with meals and meal-time doses should be skipped with any skipped meal. Approximately one month of therapy is required before a decrease in fasting blood glucose is seen. Meglitnides may have a neutral effect on weight or cause a slight increase in weight. The average weight gain caused by meglitinides appears to be lower than that caused by sulfonylureas and insulin and appears to occur only in those naïve to oral antidiabetic agents. Due to their mechanism of action, meglitinides may cause hypoglycemia although the risk is thought to be lower than that of sulfonylureas since their action is dependent on the presence of glucose. In addition to reducing postprandial and fasting blood glucose, meglitnides have been shown to decrease glycosylated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Meglitinides appear to be more effective at lowering postprandial blood glucose than metformin, sulfonylureas and thiazolidinediones. Repaglinide is extensively metabolized in the liver and excreted in bile. Repaglinide metabolites do not possess appreciable hypoglycemic activity. Approximately 90% of a single orally administered dose is eliminated in feces and 8% in urine.

生产厂家
  • Novo nordisk inc
  • Novo Nordisk Inc.
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Massi-Benedetti M, Damsbo P: Pharmacology and clinical experience with repaglinide. Expert Opin Investig Drugs. 2000 Apr;9(4):885-98. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Phenylpiperidines
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Acetates
  • Benzoates
  • Salicylates and Derivatives
  • Phenols and Derivatives
  • Amino Ketones
  • Aliphatic and Aryl Amines
  • Ethers
  • Benzene and Derivatives
  • Phenylpiperidines
  • Carboxylic Acids and Derivatives
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Carboxamides and Derivatives
  • Benzoyl Derivatives
  • Phenyl Esters
  • Anilines
  • Piperidines
适应症
Diabetes 糖尿病;
药理
Indication As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Pharmacodynamics Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential. Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations. Extracellular glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels causing membrane depolarization. When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization. High glucose concentrations cause ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels. The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules. Repaglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-dependent manner.
Mechanism of action Repaglinide activity is dependent on the presence functioning β cells and glucose. In contrast to sulfonylurea insulin secretatogogues, repaglinide has no effect on insulin release in the absence of glucose. Rather, it potentiates the effect of extracellular glucose on ATP-sensitive potassium channel and has little effect on insulin levels between meals and overnight. As such, repaglinide is more effective at reducing postprandial blood glucose levels than fasting blood glucose levels and requires a longer duration of therapy (approximately one month) before decreases in fasting blood glucose are observed. The insulinotropic effects of repaglinide are highest at intermediate glucose levels (3 to 10 mmol/L) and it does not increase insulin release already stimulated by high glucose concentrations (greater than 15 mmol/L). Repaglinide appears to be selective for pancreatic β cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue.
Absorption Rapidly and completely absorbed following oral administration. Peak plasma concentrations are observed within 1 hour (range 0.5-1.4 hours). The absolute bioavailability is approximately 56%. Maximal biological effect is observed within 3-3.5 hours and plasma insulin levels remain elevated for 4-6 hours. When a single 2 mg dose of repaglinide is given to healthy subjects, the area under the curve (AUC) is 18.0 - 18.7 (ng/mL/h)^3.
Volume of distribution

31 L following IV administration in healthy individuals
Protein binding >98% (e.g. to to albumin and α1-acid glycoprotein)
Metabolism
Repaglinide is rapidly metabolized via oxidation and dealkylation by cytochrome P450 3A4 and 2C9 to form the major dicarboxylic acid derivative (M2). Further oxidation produces the aromatic amine derivative (M1). Glucuronidation of the carboxylic acid group of repaglinide yields an acyl glucuronide (M7). Several other unidentified metabolites have been detected. Repaglinide metabolites to not possess appreciable hypoglycemic activity.

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

Substrate Enzymes Product
Repaglinide
hydroxyrepaglinide Details
Repaglinide
repaglinide aromatic amine Details
Route of elimination 90% eliminated in feces (<2% as unchanged drug), 8% in urine (0.1% as unchanged drug)
Half life 1 hour
Clearance

33-38 L/hour following IV administration
Toxicity LD50 >1 g/kg (rat) (W. Grell)
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00454 Repaglinide Pathway SMP00454
理化性质
Properties
State solid
Experimental Properties
Property Value Source
melting point 130-131 °C Not Available
logP 5.9 Not Available
Predicted Properties
Property Value Source
water solubility 2.94e-03 g/l ALOGPS
logP 5.05 ALOGPS
logP 3.95 ChemAxon
logS -5.2 ALOGPS
pKa (strongest acidic) 3.68 ChemAxon
pKa (strongest basic) 4.82 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 78.87 ChemAxon
rotatable bond count 10 ChemAxon
refractivity 131.83 ChemAxon
polarizability 51.49 ChemAxon
药物相互作用
Drug Interaction
Acebutolol Acebutolol may decrease symptoms of hypoglycemia and increase the time required for the body to compensate for hypoglycemia.
Atenolol The beta-blocker, atenolol, may decrease symptoms of hypoglycemia.
Betaxolol The beta-blocker, betaxolol, may decrease symptoms of hypoglycemia.
Bevantolol The beta-blocker, bevantolol, may decrease symptoms of hypoglycemia.
Bisoprolol The beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
Carteolol The beta-blocker, carteolol, may decrease symptoms of hypoglycemia.
Carvedilol The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.
Clarithromycin Clarithromycin may increase the effect of repaglinide.
Cyclosporine Cyclosporine may increase the therapeutic and adverse effects of repaglinide.
Erythromycin The macrolide, erythromycin, may increase the effect of repaglinide.
Esmolol The beta-blocker, esmolol, may decrease symptoms of hypoglycemia.
Fluvastatin Inhibitors of CYP3A4 and P-glycoprotein may increase serum concentrations of repaglinide. Monitor concomitant therapy closely.
Gemfibrozil Gemfibrozil may increase the effect and toxicity of repaglinide.
Glucosamine Possible hyperglycemia
Josamycin The macrolide, josamycin, may increase the effect of repaglinide.
Labetalol The beta-blocker, labetalol, may decrease symptoms of hypoglycemia.
Metoprolol The beta-blocker, metoprolol, may decrease symptoms of hypoglycemia.
Nadolol The beta-blocker, nadolol, may decrease symptoms of hypoglycemia.
Oxprenolol The beta-blocker, oxprenolol, may decrease symptoms of hypoglycemia.
Penbutolol The beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
Pindolol The beta-blocker, pindolol, may decrease symptoms of hypoglycemia.
Practolol The beta-blocker, practolol, may decrease symptoms of hypoglycemia.
Pravastatin Substrates of organic anion transporters may increase levels of repaglinide. Monitor concomitant therapy closely.
Propranolol The beta-blocker, propranolol, may decrease symptoms of hypoglycemia.
Rifampin Rifampin decreases the effect of repaglinide
Sotalol The beta-blocker, sotalol, may decrease symptoms of hypoglycemia.
Telithromycin Telithromycin may reduce clearance of Repaglinide. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Repaglinide if Telithromycin is initiated, discontinued or dose changed.
Timolol The beta-blocker, timolol, may decrease symptoms of hypoglycemia.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of repaglinide by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of repaglinide if voriconazole is initiated, discontinued or dose changed.
食物相互作用
  • Take up to 30 minutes before meals.
  • When taken with a high-fat meal, AUC and Cmax decreases.

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