You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
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 KeyBOVGTQGAOIONJV-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
Not Available
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 point180-182U.S. Patent 3,501,495
logP2.6Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.19ALOGPS
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 Area78.51 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity83.88 m3·mol-1ChemAxon
Polarizability34.17 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

U.S. Patent 3,501,495

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.

Targets

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

Enzymes

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

Carriers

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
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on April 25, 2014 11:40