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Identification
NameRepaglinide
Accession NumberDB00912  (APRD00439)
Typesmall molecule
Groupsapproved, investigational
Description

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.

Structure
Thumb
Synonyms
SynonymLanguageCode
AG-EE 388 ZWNot AvailableNot Available
AG-EE 623 ZWNot AvailableNot Available
RepaglinidaSpanishINN
RepaglinidumLatinINN
SaltsNot Available
Brand names
NameCompany
GlucoNormNovo Nordisk
PrandinNovo Nordisk
Brand mixtures
Brand NameIngredients
PrandiMet Repaglinide and Metformin
Categories
CAS number135062-02-1
WeightAverage: 452.5857
Monoisotopic: 452.26750765
Chemical FormulaC27H36N2O4
InChI KeyInChIKey=FAEKWTJYAYMJKF-QHCPKHFHSA-N
InChI
InChI=1S/C27H36N2O4/c1-4-33-25-17-20(12-13-22(25)27(31)32)18-26(30)28-23(16-19(2)3)21-10-6-7-11-24(21)29-14-8-5-9-15-29/h6-7,10-13,17,19,23H,4-5,8-9,14-16,18H2,1-3H3,(H,28,30)(H,31,32)/t23-/m0/s1
IUPAC Name
2-ethoxy-4-({[(1S)-3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl]carbamoyl}methyl)benzoic acid
SMILES
CCOC1=C(C=CC(CC(=O)N[C@@H](CC(C)C)C2=CC=CC=C2N2CCCCC2)=C1)C(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassPiperidines
SubclassPhenylpiperidines
Direct parentPhenylpiperidines
Alternative parentsPhenylpropylamines; Salicylic Acids; Benzoic Acids; Benzoyl Derivatives; Phenol Ethers; Alkyl Aryl Ethers; Tertiary Amines; Secondary Carboxylic Acid Amides; Polyamines; Carboxylic Acids; Enolates
Substituentsphenylpropylamine; salicylic acid; salicylic acid or derivative; benzoic acid or derivative; benzoic acid; benzoyl; phenol ether; alkyl aryl ether; benzene; carboxamide group; tertiary amine; secondary carboxylic acid amide; polyamine; ether; carboxylic acid; enolate; carboxylic acid derivative; amine; organonitrogen compound
Classification descriptionThis compound belongs to the phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
Pharmacology
IndicationAs an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
PharmacodynamicsInsulin 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 actionRepaglinide 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.
AbsorptionRapidly 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.

SubstrateEnzymesProduct
Repaglinide
hydroxyrepaglinideDetails
Repaglinide
repaglinide aromatic amineDetails
Route of elimination90% eliminated in feces (<2% as unchanged drug), 8% in urine (0.1% as unchanged drug)
Half life1 hour
Clearance

33-38 L/hour following IV administration

ToxicityLD50 >1 g/kg (rat) (W. Grell)
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Repaglinide Action PathwayDrug actionSMP00454
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9172
Blood Brain Barrier - 0.7101
Caco-2 permeable - 0.5891
P-glycoprotein substrate Substrate 0.8145
P-glycoprotein inhibitor I Inhibitor 0.6044
P-glycoprotein inhibitor II Inhibitor 0.6868
Renal organic cation transporter Non-inhibitor 0.849
CYP450 2C9 substrate Non-substrate 0.8288
CYP450 2D6 substrate Non-substrate 0.9117
CYP450 3A4 substrate Substrate 0.7019
CYP450 1A2 substrate Non-inhibitor 0.9206
CYP450 2C9 substrate Non-inhibitor 0.907
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.9264
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8682
Ames test Non AMES toxic 0.8136
Carcinogenicity Non-carcinogens 0.8004
Biodegradation Not ready biodegradable 0.919
Rat acute toxicity 2.4497 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9605
hERG inhibition (predictor II) Non-inhibitor 0.5272
Pharmacoeconomics
Manufacturers
  • Novo nordisk inc
  • Novo Nordisk Inc.
Packagers
Dosage forms
FormRouteStrength
TabletOral0.5 mg
TabletOral1 mg
TabletOral2 mg
Prices
Unit descriptionCostUnit
Prandin 1 mg tablet2.48USDtablet
Prandin 0.5 mg tablet2.47USDtablet
Prandin 2 mg tablet2.33USDtablet
Gluconorm 2 mg Tablet0.34USDtablet
Gluconorm 1 mg Tablet0.32USDtablet
Gluconorm 0.5 mg Tablet0.31USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States66773581998-06-122018-06-12
Canada21118512002-02-262011-06-21
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point130-131 °CNot Available
logP5.9Not Available
Predicted Properties
PropertyValueSource
water solubility2.94e-03 g/lALOGPS
logP5.05ALOGPS
logP3.95ChemAxon
logS-5.2ALOGPS
pKa (strongest acidic)3.68ChemAxon
pKa (strongest basic)4.82ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count2ChemAxon
polar surface area78.87ChemAxon
rotatable bond count10ChemAxon
refractivity131.83ChemAxon
polarizability51.49ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Manne Reddy, “Polymorphic forms of (S)-Repaglinide and the processes for preparation thereof.” U.S. Patent US20040102477, issued May 27, 2004.

US20040102477
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
External Links
ResourceLink
KEGG DrugD00594
KEGG CompoundC07670
PubChem Compound65981
PubChem Substance46508150
ChemSpider59377
BindingDB50153520
Therapeutic Targets DatabaseDAP000133
PharmGKBPA451234
Drug Product Database2239925
RxListhttp://www.rxlist.com/cgi/generic/prandin.htm
Drugs.comhttp://www.drugs.com/cdi/repaglinide.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/pra1343.shtml
WikipediaRepaglinide
ATC CodesA10BX02
AHFS Codes
  • 68:20.16
PDB EntriesNot Available
FDA labelshow(175 KB)
MSDSshow(57.3 KB)
Interactions
Drug Interactions
Drug
AcebutololAcebutolol may decrease symptoms of hypoglycemia and increase the time required for the body to compensate for hypoglycemia.
AtenololThe beta-blocker, atenolol, may decrease symptoms of hypoglycemia.
BetaxololThe beta-blocker, betaxolol, may decrease symptoms of hypoglycemia.
BevantololThe beta-blocker, bevantolol, may decrease symptoms of hypoglycemia.
BisoprololThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
CarteololThe beta-blocker, carteolol, may decrease symptoms of hypoglycemia.
CarvedilolThe beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.
ClarithromycinClarithromycin may increase the effect of repaglinide.
CyclosporineCyclosporine may increase the therapeutic and adverse effects of repaglinide.
ErythromycinThe macrolide, erythromycin, may increase the effect of repaglinide.
EsmololThe beta-blocker, esmolol, may decrease symptoms of hypoglycemia.
FluvastatinInhibitors of CYP3A4 and P-glycoprotein may increase serum concentrations of repaglinide. Monitor concomitant therapy closely.
GemfibrozilGemfibrozil may increase the effect and toxicity of repaglinide.
GlucosaminePossible hyperglycemia
JosamycinThe macrolide, josamycin, may increase the effect of repaglinide.
LabetalolThe beta-blocker, labetalol, may decrease symptoms of hypoglycemia.
MetoprololThe beta-blocker, metoprolol, may decrease symptoms of hypoglycemia.
NadololThe beta-blocker, nadolol, may decrease symptoms of hypoglycemia.
OxprenololThe beta-blocker, oxprenolol, may decrease symptoms of hypoglycemia.
PenbutololThe beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
PindololThe beta-blocker, pindolol, may decrease symptoms of hypoglycemia.
PractololThe beta-blocker, practolol, may decrease symptoms of hypoglycemia.
PravastatinSubstrates of organic anion transporters may increase levels of repaglinide. Monitor concomitant therapy closely.
PropranololThe beta-blocker, propranolol, may decrease symptoms of hypoglycemia.
RifampicinRifampin decreases the effect of repaglinide
SotalolThe beta-blocker, sotalol, may decrease symptoms of hypoglycemia.
TelithromycinTelithromycin 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.
TimololThe beta-blocker, timolol, may decrease symptoms of hypoglycemia.
VoriconazoleVoriconazole, 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.
Food Interactions
  • Take up to 30 minutes before meals.
  • When taken with a high-fat meal, AUC and Cmax decreases.

1. ATP-binding cassette sub-family C member 8

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
ATP-binding cassette sub-family C member 8 Q09428 Details

References:

  1. Hu S, Wang S, Fanelli B, Bell PA, Dunning BE, Geisse S, Schmitz R, Boettcher BR: Pancreatic beta-cell K(ATP) channel activity and membrane-binding studies with nateglinide: A comparison with sulfonylureas and repaglinide. J Pharmacol Exp Ther. 2000 May;293(2):444-52. Pubmed
  2. Sunaga Y, Gonoi T, Shibasaki T, Ichikawa K, Kusama H, Yano H, Seino S: The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide. Eur J Pharmacol. 2001 Nov 9;431(1):119-25. Pubmed
  3. Hansen AM, Christensen IT, Hansen JB, Carr RD, Ashcroft FM, Wahl P: Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1. Diabetes. 2002 Sep;51(9):2789-95. Pubmed
  4. Wangler B, Schneider S, Thews O, Schirrmacher E, Comagic S, Feilen P, Schwanstecher C, Schwanstecher M, Shiue CY, Alavi A, Hohnemann S, Piel M, Rosch F, Schirrmacher R: Synthesis and evaluation of (S)-2-(2-[18F]fluoroethoxy)-4-([3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl -carbamoyl]-methyl)-benzoic acid ([18F]repaglinide): a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography (PET). Nucl Med Biol. 2004 Jul;31(5):639-47. Pubmed
  5. Wangler B, Beck C, Shiue CY, Schneider S, Schwanstecher C, Schwanstecher M, Feilen PJ, Alavi A, Rosch F, Schirrmacher R: Synthesis and in vitro evaluation of (S)-2-([11C]methoxy)-4-[3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbam oyl]-benzoic acid ([11C]methoxy-repaglinide): a potential beta-cell imaging agent. Bioorg Med Chem Lett. 2004 Oct 18;14(20):5205-9. Pubmed
  6. Dornhorst A: Insulinotropic meglitinide analogues. Lancet. 2001 Nov 17;358(9294):1709-16. Pubmed

2. Peroxisome proliferator-activated receptor gamma

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: agonist

Components

Name UniProt ID Details
Peroxisome proliferator-activated receptor gamma P37231 Details

References:

  1. Scarsi M, Podvinec M, Roth A, Hug H, Kersten S, Albrecht H, Schwede T, Meyer UA, Rucker C: Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Mol Pharmacol. 2007 Feb;71(2):398-406. Epub 2006 Nov 2. Pubmed

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  3. Bidstrup TB, Bjornsdottir I, Sidelmann UG, Thomsen MS, Hansen KT: CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol. 2003 Sep;56(3):305-14. Pubmed

2. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  4. Bidstrup TB, Bjornsdottir I, Sidelmann UG, Thomsen MS, Hansen KT: CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol. 2003 Sep;56(3):305-14. Pubmed

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. Novo Nordisk. Prandin® (repaglinide) tablets prescribing information. Princeton, NJ; 2010 Mar 19.

1. Solute carrier organic anion transporter family member 1B1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B1 Q9Y6L6 Details

References:

  1. He J, Qiu Z, Li N, Yu Y, Lu Y, Han D, Li T, Zhao D, Sun W, Fang F, Zheng J, Fan H, Chen X: Effects of SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of repaglinide in healthy Chinese volunteers. Eur J Clin Pharmacol. 2011 Jul;67(7):701-7. doi: 10.1007/s00228-011-0994-7. Epub 2011 Feb 17. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12