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Identification
NameGliclazide
Accession NumberDB01120  (APRD00460)
Typesmall molecule
Groupsapproved
Description

Gliclazide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It belongs to the sulfonylurea class of insulin secretagogues, which act by stimulating β cells of the pancreas to release insulin. Sulfonylureas increase both basal insulin secretion and meal-stimulated insulin release. Medications in this class differ in their dose, rate of absorption, duration of action, route of elimination and binding site on their target pancreatic β cell receptor. Sulfonylureas also increase peripheral glucose utilization, decrease hepatic gluconeogenesis and may increase the number and sensitivity of insulin receptors. Sulfonylureas are associated with weight gain, though less so than insulin. Due to their mechanism of action, sulfonylureas may cause hypoglycemia and require consistent food intake to decrease this risk. The risk of hypoglycemia is increased in elderly, debilitated and malnourished individuals. Gliclazide has been shown to decrease fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels (reflective of the last 8-10 weeks of glucose control). Gliclazide is extensively metabolized by the liver; its metabolites are excreted in both urine (60-70%) and feces (10-20%).

Structure
Thumb
Synonyms
SynonymLanguageCode
1-(3-Azabicyclo(3.3.0)oct-3-yl)-3-(p-tolylsulfonyl)ureaNot AvailableNot Available
1-(Hexahydrocyclopenta(c)pyrrol-2(1H)-yl)-3-(p-tolylsulfonyl)ureaNot AvailableNot Available
GliclazidaSpanishINN
GliclazidumLatinINN
N-(4-Methylbenzenesulfonyl)-N'-(3-azabicyclo(3.3.0)oct-3-yl)ureaNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
DiamicronServier
Diamicron MRServier
GlimicronNot Available
Mylan-GliclazideMylan
NordialexNot Available
PMS-GliclazidePharmascience
Brand mixturesNot Available
Categories
CAS number21187-98-4
WeightAverage: 323.411
Monoisotopic: 323.130362243
Chemical FormulaC15H21N3O3S
InChI KeyInChIKey=BOVGTQGAOIONJV-BETUJISGNA-N
InChI
InChI=1/C15H21N3O3S/c1-11-5-7-14(8-6-11)22(20,21)17-15(19)16-18-9-12-3-2-4-13(12)10-18/h5-8,12-13H,2-4,9-10H2,1H3,(H2,16,17,19)/t12-,13+
IUPAC Name
3-[(3aR,6aS)-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-methylbenzenesulfonyl)urea
SMILES
[H][C@@]12CCC[C@]1([H])CN(C2)NC(=O)NS(=O)(=O)C1=CC=C(C)C=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassBenzenesulfonamides
Direct parentBenzenesulfonamides
Alternative parentsToluenes; Sulfonylureas; Sulfonamides; Sulfonyls; Semicarbazides; Pyrrolidines; Cyclic Alcohols and Derivatives; Polyamines
Substituentssulfonylurea; toluene; cyclic alcohol; pyrrolidine; sulfonyl; semicarbazide; sulfonamide; sulfonic acid derivative; polyamine; amine; hydrazine derivative; organonitrogen compound
Classification descriptionThis compound belongs to the benzenesulfonamides. These are organic compounds containing a sulfonamide group that is S-linked to a benzene ring.
Pharmacology
IndicationFor the treatment of NIDDM in conjunction with diet and exercise.
PharmacodynamicsGliclazide is a second generation sulphonylurea which acts as a hypoglycemic agent. It stimulates β cells of the islet of Langerhans in the pancreas to release insulin. It also enhances peripheral insulin sensitivity. Overall, it potentiates insulin release and improves insulin dynamics.
Mechanism of actionGliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels. The binding results in closure of the channels and leads to a resulting decrease in potassium efflux leads to depolarization of the β cells. This opens voltage-dependent calcium channels in the β cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretorty granules.
AbsorptionRapidly and well absorbed but may have wide inter- and intra-individual variability. Peak plasma concentrations occur within 4-6 hours of oral administration.
Volume of distributionNot Available
Protein binding94%, highly bound to plasma proteins
Metabolism

Extensively metabolized in the liver. Less than 1% of the orally administered dose appears unchanged in the urine. Metabolites include oxidized and hydroxylated derivates, as well as glucuronic acid conjugates.

SubstrateEnzymesProduct
Gliclazide
7-β-HydroxygliclazideDetails
Gliclazide
6-β-HydroxygliclazideDetails
Gliclazide
MethylhydroxygliclazideDetails
Methylhydroxygliclazide
    CarboxygliclazideDetails
    Gliclazide
    7-α-HydroxygliclazideDetails
    Gliclazide
    6-α-HydroxygliclazideDetails
    Route of eliminationMetabolites and conjugates are eliminated primarily by the kidneys (60-70%) and also in the feces (10-20%).
    Half life10.4 hours. Duration of action is 10-24 hours.
    ClearanceNot Available
    ToxicityLD50=3000 mg/kg (orally in mice). Gliclazide and its metabolites may accumulate in those with severe hepatic and/or renal dysfunction. Symptoms of hypoglycemia include: dizziness, lack of energy, drowsiness, headache and sweating.
    Affected organisms
    • Humans and other mammals
    Pathways
    PathwayCategorySMPDB ID
    Gliclazide Action PathwayDrug actionSMP00461
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.9944
    Blood Brain Barrier + 0.8445
    Caco-2 permeable - 0.6543
    P-glycoprotein substrate Substrate 0.6982
    P-glycoprotein inhibitor I Non-inhibitor 0.8619
    P-glycoprotein inhibitor II Non-inhibitor 0.931
    Renal organic cation transporter Non-inhibitor 0.8178
    CYP450 2C9 substrate Substrate 0.6226
    CYP450 2D6 substrate Non-substrate 0.9116
    CYP450 3A4 substrate Non-substrate 0.6925
    CYP450 1A2 substrate Non-inhibitor 0.9046
    CYP450 2C9 substrate Non-inhibitor 0.9071
    CYP450 2D6 substrate Non-inhibitor 0.9231
    CYP450 2C19 substrate Non-inhibitor 0.9025
    CYP450 3A4 substrate Non-inhibitor 0.9218
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8751
    Ames test Non AMES toxic 0.8047
    Carcinogenicity Non-carcinogens 0.7944
    Biodegradation Not ready biodegradable 0.7997
    Rat acute toxicity 2.0016 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.5992
    hERG inhibition (predictor II) Non-inhibitor 0.8064
    Pharmacoeconomics
    Manufacturers
    PackagersNot Available
    Dosage forms
    FormRouteStrength
    TabletOral80 mg
    Tablet, extended releaseOral30 mg
    Tablet, extended releaseOral60 mg
    Prices
    Unit descriptionCostUnit
    Diamicron 80 mg Tablet0.42USDtablet
    Apo-Gliclazide 80 mg Tablet0.23USDtablet
    Gliclazide 80 mg Tablet0.23USDtablet
    Mylan-Gliclazide 80 mg Tablet0.23USDtablet
    Novo-Gliclazide 80 mg Tablet0.23USDtablet
    Pms-Gliclazide 80 mg Tablet0.23USDtablet
    Diamicron Mr 30 mg Sustained-Release Tablet0.16USDtablet
    Apo-Gliclazide Mr 30 mg Sustained-Release Tablet0.15USDtablet
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    Canada22734202002-07-092019-05-27
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point181 °CPhysProp
    logP2.6Not Available
    Predicted Properties
    PropertyValueSource
    water solubility1.90e-01 g/lALOGPS
    logP1.52ALOGPS
    logP1.73ChemAxon
    logS-3.2ALOGPS
    pKa (strongest acidic)4.07ChemAxon
    pKa (strongest basic)1.38ChemAxon
    physiological charge-1ChemAxon
    hydrogen acceptor count4ChemAxon
    hydrogen donor count2ChemAxon
    polar surface area78.51ChemAxon
    rotatable bond count2ChemAxon
    refractivity83.88ChemAxon
    polarizability34.17ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis ReferenceNot Available
    General ReferenceNot Available
    External Links
    ResourceLink
    KEGG DrugD01599
    ChEBI31654
    ChEMBLCHEMBL427216
    Therapeutic Targets DatabaseDAP000522
    PharmGKBPA10892
    Drug Product Database2248453
    WikipediaGliclazide
    ATC CodesA10BB09
    AHFS Codes
    • 68:20.20
    PDB EntriesNot Available
    FDA labelNot Available
    MSDSshow(57.5 KB)
    Interactions
    Drug Interactions
    Drug
    AcebutololAcebutolol may decrease symptoms of hypoglycemia and increase the time required for the body to compensate for hypoglycemia.
    Acetylsalicylic acidAcetylsalicylic acid increases the effect of the sulfonylurea, gliclazide.
    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.
    Bismuth SubsalicylateThe salicylate, bismuth subsalicylate, increases the effect of the sulfonylurea, gliclazide.
    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.
    ChloramphenicolChloramphenicol may increase the effect of sulfonylurea, gliclazide.
    ClofibrateClofibrate may increase the effect of sulfonylurea, gliclazide.
    DicoumarolDicumarol may increase the effect of sulfonylurea, gliclazide.
    EsmololThe beta-blocker, esmolol, may decrease symptoms of hypoglycemia.
    GlucosaminePossible hyperglycemia
    LabetalolThe beta-blocker, labetalol, may decrease symptoms of hypoglycemia.
    Magnesium salicylateThe salicylate, magnesium salicylate, increases the effect of the sulfonylurea, gliclazide.
    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.
    PhenylbutazonePhenylbutazone increases the effect of the hypoglycemic agent
    PindololThe beta-blocker, pindolol, may decrease symptoms of hypoglycemia.
    PractololThe beta-blocker, practolol, may decrease symptoms of hypoglycemia.
    PropranololThe beta-blocker, propranolol, may decrease symptoms of hypoglycemia.
    RifampicinRifampin may decrease the effect of sulfonylurea, gliclazide.
    Salicylate-sodiumThe salicylate, salicylate-sodium, increases the effect of the sulfonylurea, gliclazide.
    SalsalateThe salicylate, salsalate, increases the effect of the sulfonylurea, gliclazide.
    Somatropin recombinantSomatropin may antagonize the hypoglycemic effect of gliclazide. Monitor for changes in fasting and postprandial blood sugars.
    SotalolThe beta-blocker, sotalol, may decrease symptoms of hypoglycemia.
    TimololThe beta-blocker, timolol, may decrease symptoms of hypoglycemia.
    Trisalicylate-cholineThe salicylate, trisalicylate-choline, increases the effect of the sulfonylurea, gliclazide.
    Food Interactions
    • Avoid alcohol.
    • Take without regard to meals. A consistent diet is recommended to reduce the risk of hypoglycemia.

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

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: binder

    Components

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

    References:

    1. Gribble FM, Ashcroft FM: Sulfonylurea sensitivity of adenosine triphosphate-sensitive potassium channels from beta cells and extrapancreatic tissues. Metabolism. 2000 Oct;49(10 Suppl 2):3-6. Pubmed
    2. Harrower A: Gliclazide modified release: from once-daily administration to 24-hour blood glucose control. Metabolism. 2000 Oct;49(10 Suppl 2):7-11. Pubmed
    3. Lawrence CL, Proks P, Rodrigo GC, Jones P, Hayabuchi Y, Standen NB, Ashcroft FM: Gliclazide produces high-affinity block of KATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells. Diabetologia. 2001 Aug;44(8):1019-25. Pubmed
    4. Reimann F, Ashcroft FM, Gribble FM: Structural basis for the interference between nicorandil and sulfonylurea action. Diabetes. 2001 Oct;50(10):2253-9. Pubmed
    5. Proks P, Reimann F, Green N, Gribble F, Ashcroft F: Sulfonylurea stimulation of insulin secretion. Diabetes. 2002 Dec;51 Suppl 3:S368-76. Pubmed

    2. Vascular endothelial growth factor A

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: other/unknown

    Components

    Name UniProt ID Details
    Vascular endothelial growth factor A P15692 Details

    References:

    1. Mamputu JC, Renier G: Advanced glycation end products increase, through a protein kinase C-dependent pathway, vascular endothelial growth factor expression in retinal endothelial cells. Inhibitory effect of gliclazide. J Diabetes Complications. 2002 Jul-Aug;16(4):284-93. Pubmed
    2. Mamputu JC, Renier G: Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazide. Diabetes Obes Metab. 2004 Mar;6(2):95-103. Pubmed
    3. Li L, Renier G: Activation of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase by advanced glycation end products links oxidative stress to altered retinal vascular endothelial growth factor expression. Metabolism. 2006 Nov;55(11):1516-23. Pubmed
    4. Kimura T, Takagi H, Suzuma K, Kita M, Watanabe D, Yoshimura N: Comparisons between the beneficial effects of different sulphonylurea treatments on ischemia-induced retinal neovascularization. Free Radic Biol Med. 2007 Aug 1;43(3):454-61. Epub 2007 May 3. 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. 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. Cytochrome P450 2C19

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate inhibitor

    Components

    Name UniProt ID Details
    Cytochrome P450 2C19 P33261 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

    1. Serum albumin

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Components

    Name UniProt ID Details
    Serum albumin P02768 Details

    References:

    1. Igaki A, Kobayashi K, Kimura M, Sakoguchi T, Matsuoka A: Influence of blood proteins on biomedical analysis. XII. Effects of glycation on gliclazide (oral hypoglycemic drug)-binding with serum albumin in diabetics. Chem Pharm Bull (Tokyo). 1992 Jan;40(1):255-7. Pubmed
    2. Kobayashi K, Kimura M, Sakoguchi T, Hase A, Matsuoka A: Influence of blood proteins on biomedical analysis. V. Effect of ethyl alcohol on gliclazide-binding with bovine serum albumin. Chem Pharm Bull (Tokyo). 1982 Mar;30(3):1077-80. Pubmed

    Comments
    Drug created on June 13, 2005 07:24 / Updated on November 23, 2013 09:43