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Identification
NameNateglinide
Accession NumberDB00731  (APRD00593)
Typesmall molecule
Groupsapproved, investigational
Description

Nateglinide 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. Nateglinide is an amino acid derivative that 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. Nateglinide is extensively metabolized in the liver and excreted in urine (83%) and feces (10%). The major metabolites possess less activity than the parent compound. One minor metabolite, the isoprene, has the same potency as its parent compound.

Structure
Thumb
SynonymsNot Available
Salts
Name/CAS Structure Properties
SDZ-DJN 608
Thumb Not applicable DBSALT000922
Brand names
NameCompany
FasticNot Available
StarlixNovartis
StarsisNot Available
Brand mixturesNot Available
Categories
CAS number105816-04-4
WeightAverage: 317.4226
Monoisotopic: 317.199093735
Chemical FormulaC19H27NO3
InChI KeyInChIKey=OELFLUMRDSZNSF-YJEKIOLLSA-N
InChI
InChI=1S/C19H27NO3/c1-13(2)15-8-10-16(11-9-15)18(21)20-17(19(22)23)12-14-6-4-3-5-7-14/h3-7,13,15-17H,8-12H2,1-2H3,(H,20,21)(H,22,23)/t15?,16-,17-/m1/s1
IUPAC Name
(2R)-3-phenyl-2-{[4-(propan-2-yl)cyclohexyl]formamido}propanoic acid
SMILES
CC(C)C1CC[C@@H](CC1)C(=O)N[C@H](CC1=CC=CC=C1)C(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentN-acyl-alpha Amino Acids
Alternative parentsPhenylpropanoic Acids; Aromatic Monoterpenes; Amphetamines and Derivatives; Amino Fatty Acids; Secondary Carboxylic Acid Amides; Carboxylic Acids; Polyamines; Enolates
Substituents3-phenylpropanoic-acid; monoterpene; amphetamine or derivative; limonane-,terpinane-,phellandrane monoterpene; aromatic monoterpene; benzene; secondary carboxylic acid amide; carboxamide group; enolate; polyamine; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the n-acyl-alpha amino acids. These are compounds containing an alpha amino acid which bears an acyl group at his terminal nitrogen atom.
Pharmacology
IndicationFor the treatment of non-insulin dependent-diabetes mellitus in conjunction with diet and exercise.
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. Nateglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-dependent manner.
Mechanism of actionNateglinide activity is dependent on the presence functioning β cells and glucose. In contrast to sulfonylurea insulin secretatogogues, nateglinide 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, nateglinide 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 nateglinide 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). Nateglinide appears to be selective for pancreatic β cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue.
AbsorptionRapidly absorbed following oral administration prior to a meal, absolute bioavailability is estimated to be approximately 73%. Peak plasma concentrations generally occur within 1 hour of oral administration. Onset of action is <20 minutes and the duration of action is approximately 4 hours.
Volume of distribution

10 liters in healthy subjects

Protein binding98% bound to serum proteins, primarily serum albumin and to a lesser extent α1 acid glycoprotein
Metabolism

Hepatic, via cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%). Metabolism is via hydroxylation followed by glucuronidation. The major metabolites have less antidiabetic activity than nateglinide, but the isoprene minor metabolite has antidiabetic activity comparable to that of nateglinide.

SubstrateEnzymesProduct
Nateglinide
Nateglinide metabolite M2/M3Details
Nateglinide metabolite M2/M3
    Nateglinide metabolite M11/M12Details
    Nateglinide
    Nateglinide metabolite M1Details
    Nateglinide metabolite M1
      Nateglinide metabolite M11/M12Details
      Nateglinide
        Nateglinide metabolite M7Details
        Nateglinide metabolite M7
          Nateglinide metabolite M11/M12Details
          Nateglinide
          Nateglinide glucuronide and isomers (M4/M5/M6)Details
          Route of eliminationUrine (83%) and feces (10%)
          Half life1.5 hours
          ClearanceNot Available
          ToxicityAn overdose may result in an exaggerated glucose-lowering effect with the development of hypoglycemic symptoms.
          Affected organisms
          • Humans and other mammals
          Pathways
          PathwayCategorySMPDB ID
          Nateglinide Action PathwayDrug actionSMP00453
          SNP Mediated EffectsNot Available
          SNP Mediated Adverse Drug ReactionsNot Available
          ADMET
          Predicted ADMET features
          Property Value Probability
          Human Intestinal Absorption + 0.9156
          Blood Brain Barrier + 0.7539
          Caco-2 permeable - 0.7148
          P-glycoprotein substrate Substrate 0.6187
          P-glycoprotein inhibitor I Non-inhibitor 0.8842
          P-glycoprotein inhibitor II Non-inhibitor 0.8604
          Renal organic cation transporter Non-inhibitor 0.8882
          CYP450 2C9 substrate Non-substrate 0.7192
          CYP450 2D6 substrate Non-substrate 0.9116
          CYP450 3A4 substrate Non-substrate 0.5103
          CYP450 1A2 substrate Non-inhibitor 0.9167
          CYP450 2C9 substrate Non-inhibitor 0.8412
          CYP450 2D6 substrate Non-inhibitor 0.9088
          CYP450 2C19 substrate Non-inhibitor 0.8764
          CYP450 3A4 substrate Non-inhibitor 0.8874
          CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8734
          Ames test Non AMES toxic 0.922
          Carcinogenicity Non-carcinogens 0.9354
          Biodegradation Not ready biodegradable 0.7779
          Rat acute toxicity 2.0362 LD50, mol/kg Not applicable
          hERG inhibition (predictor I) Weak inhibitor 0.9881
          hERG inhibition (predictor II) Non-inhibitor 0.8425
          Pharmacoeconomics
          Manufacturers
          • Dr reddys laboratories ltd
          • Par pharmaceutical inc
          • Teva pharmaceuticals usa
          • Novartis pharmaceuticals corp
          Packagers
          Dosage forms
          FormRouteStrength
          TabletOral120 mg
          TabletOral60 mg
          Prices
          Unit descriptionCostUnit
          Starlix 120 mg tablet2.12USDtablet
          Starlix 60 mg tablet2.01USDtablet
          Nateglinide 120 mg tablet1.73USDtablet
          Nateglinide 60 mg tablet1.66USDtablet
          DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
          Patents
          CountryPatent NumberApprovedExpires (estimated)
          United States65591882000-09-152020-09-15
          United StatesRE348781992-09-082009-09-08
          Canada22718652003-10-142017-11-14
          Canada21146781999-04-272014-02-01
          Properties
          Statesolid
          Experimental Properties
          PropertyValueSource
          water solubilityPractically insolubleNot Available
          logP2.4Not Available
          Predicted Properties
          PropertyValueSource
          water solubility8.48e-03 g/lALOGPS
          logP3.59ALOGPS
          logP4.03ChemAxon
          logS-4.6ALOGPS
          pKa (strongest acidic)4ChemAxon
          pKa (strongest basic)-0.38ChemAxon
          physiological charge-1ChemAxon
          hydrogen acceptor count3ChemAxon
          hydrogen donor count2ChemAxon
          polar surface area66.4ChemAxon
          rotatable bond count6ChemAxon
          refractivity89.46ChemAxon
          polarizability35.57ChemAxon
          number of rings2ChemAxon
          bioavailability1ChemAxon
          rule of fiveYesChemAxon
          Ghose filterYesChemAxon
          Veber's ruleNoChemAxon
          MDDR-like ruleNoChemAxon
          Spectra
          SpectraNot Available
          References
          Synthesis Reference

          Michito Sumikawa, “Methods for producing nateglinide B-type crystals.” U.S. Patent US20030229249, issued December 11, 2003.

          US20030229249
          General ReferenceNot Available
          External Links
          ResourceLink
          KEGG DrugD01111
          KEGG CompoundC12508
          ChEBI146727
          ChEMBLCHEMBL783
          Therapeutic Targets DatabaseDAP000918
          PharmGKBPA450600
          Drug Product Database2245439
          RxListhttp://www.rxlist.com/cgi/generic2/nateglinide.htm
          Drugs.comhttp://www.drugs.com/cdi/nateglinide.html
          PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/sta1565.shtml
          WikipediaNateglinide
          ATC CodesA10BX03
          AHFS Codes
          • 68:20.16
          PDB EntriesNot Available
          FDA labelshow(56.5 KB)
          MSDSNot Available
          Interactions
          Drug Interactions
          Drug
          GlucosaminePossible hyperglycemia
          Somatropin recombinantSomatropin may antagonize the hypoglycemic effect of nateglinide. Monitor for changes in fasting and postprandial blood sugars.
          TelithromycinTelithromycin may reduce clearance of Nateglenide. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Nateglenide if Telithromycin is initiated, discontinued or dose changed.
          TolbutamideTolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Nateglinide. Consider alternate therapy or monitor for changes in Nateglinide therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
          VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of nateglinide by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nateglinide if voriconazole is initiated, discontinued or dose changed.
          Food Interactions
          • Take upto 30 minutes before meals.

          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. Chachin M, Yamada M, Fujita A, Matsuoka T, Matsushita K, Kurachi Y: Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety, specifically inhibits pancreatic beta-cell-type K(ATP) channels. J Pharmacol Exp Ther. 2003 Mar;304(3):1025-32. Pubmed
          5. Norman P, Rabasseda X: Nateglinide: A structurally novel, short-acting, hypoglycemic agent. Drugs Today (Barc). 2001 Jun;37(6):411-426. 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 2C9

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Cytochrome P450 2C9 P11712 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

          2. Cytochrome P450 3A4

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Cytochrome P450 3A4 P08684 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

          3. Cytochrome P450 3A5

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Cytochrome P450 3A5 P20815 Details

          References:

          1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

          4. Cytochrome P450 3A7

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Cytochrome P450 3A7 P24462 Details

          References:

          1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

          5. Prostaglandin G/H synthase 1

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Prostaglandin G/H synthase 1 P23219 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

          6. UDP-glucuronosyltransferase 1-9

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          UDP-glucuronosyltransferase 1-9 O60656 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

          7. Cytochrome P450 2D6

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Cytochrome P450 2D6 P10635 Details

          References:

          1. 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

          1. Serum albumin

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Components

          Name UniProt ID Details
          Serum albumin P02768 Details

          References:

          1. Novartis. Starlix® (nateglinide) tablets prescribing information. East Hanover, NJ; 2009 Nov.

          2. Alpha-1-acid glycoprotein 1

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Components

          Name UniProt ID Details
          Alpha-1-acid glycoprotein 1 P02763 Details

          References:

          1. Novartis. Starlix® (nateglinide) tablets prescribing information. East Hanover, NJ; 2009 Nov.

          1. Multidrug resistance-associated protein 4

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Multidrug resistance-associated protein 4 O15439 Details

          References:

          1. Uchida Y, Kamiie J, Ohtsuki S, Terasaki T: Multichannel liquid chromatography-tandem mass spectrometry cocktail method for comprehensive substrate characterization of multidrug resistance-associated protein 4 transporter. Pharm Res. 2007 Dec;24(12):2281-96. Epub 2007 Oct 16. Pubmed

          2. Monocarboxylate transporter 1

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Monocarboxylate transporter 1 P53985 Details

          References:

          1. Okamura A, Emoto A, Koyabu N, Ohtani H, Sawada Y: Transport and uptake of nateglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1. Br J Pharmacol. 2002 Oct;137(3):391-9. Pubmed

          3. Solute carrier family 15 member 1

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: inhibitor

          Components

          Name UniProt ID Details
          Solute carrier family 15 member 1 P46059 Details

          References:

          1. Terada T, Sawada K, Saito H, Hashimoto Y, Inui K: Inhibitory effect of novel oral hypoglycemic agent nateglinide (AY4166) on peptide transporters PEPT1 and PEPT2. Eur J Pharmacol. 2000 Mar 24;392(1-2):11-7. Pubmed

          4. Solute carrier family 15 member 2

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: inhibitor

          Components

          Name UniProt ID Details
          Solute carrier family 15 member 2 Q16348 Details

          References:

          1. Terada T, Sawada K, Saito H, Hashimoto Y, Inui K: Inhibitory effect of novel oral hypoglycemic agent nateglinide (AY4166) on peptide transporters PEPT1 and PEPT2. Eur J Pharmacol. 2000 Mar 24;392(1-2):11-7. Pubmed

          5. Solute carrier family 22 member 6

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: inhibitor

          Components

          Name UniProt ID Details
          Solute carrier family 22 member 6 Q4U2R8 Details

          References:

          1. Uwai Y, Saito H, Hashimoto Y, Inui K: Inhibitory effect of anti-diabetic agents on rat organic anion transporter rOAT1. Eur J Pharmacol. 2000 Jun 16;398(2):193-7. Pubmed

          Comments
          Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11