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Identification
NameGlipizide
Accession NumberDB01067  (APRD00436)
Typesmall molecule
Groupsapproved
Description

An oral hypoglycemic agent which is rapidly absorbed and completely metabolized. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
GlipizidaSpanishINN
GlipizidumLatinINN
SaltsNot Available
Brand names
NameCompany
GlucotrolPfizer
Glucotrol XLPfizer
Brand mixturesNot Available
Categories
CAS number29094-61-9
WeightAverage: 445.535
Monoisotopic: 445.178375067
Chemical FormulaC21H27N5O4S
InChI KeyInChIKey=ZJJXGWJIGJFDTL-UHFFFAOYSA-N
InChI
InChI=1S/C21H27N5O4S/c1-15-13-24-19(14-23-15)20(27)22-12-11-16-7-9-18(10-8-16)31(29,30)26-21(28)25-17-5-3-2-4-6-17/h7-10,13-14,17H,2-6,11-12H2,1H3,(H,22,27)(H2,25,26,28)
IUPAC Name
N-[2-(4-{[(cyclohexylcarbamoyl)amino]sulfonyl}phenyl)ethyl]-5-methylpyrazine-2-carboxamide
SMILES
CC1=CN=C(C=N1)C(=O)NCCC1=CC=C(C=C1)S(=O)(=O)NC(=O)NC1CCCCC1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassBenzenesulfonamides
Direct parentBenzenesulfonamides
Alternative parentsPyrazinecarboxamides; Phenethylamines; Sulfonylureas; Sulfonyls; Sulfonamides; Secondary Carboxylic Acid Amides; Polyamines; Enolates; Carboxylic Acids
Substituentssulfonylurea; pyrazine; sulfonyl; sulfonic acid derivative; sulfonamide; secondary carboxylic acid amide; carboxamide group; carboxylic acid derivative; polyamine; enolate; carboxylic acid; amine; 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 use as an adjunct to diet for the control of hyperglycemia and its associated symptomatology in patients with non-insulin-dependent diabetes mellitus (NIDDM; type II), formerly known as maturity-onset diabetes, after an adequate trial of dietary therapy has proved unsatisfactory.
PharmacodynamicsGlipizide, a second-generation sulfonylurea, is used with diet to lower blood glucose in patients with diabetes mellitus type II. The primary mode of action of glipizide in experimental animals appears to be the stimulation of insulin secretion from the beta cells of pancreatic islet tissue and is thus dependent on functioning beta cells in the pancreatic islets. In humans glipizide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including glipizide.
Mechanism of actionSulfonylureas likely bind to ATP-sensitive potassium-channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin.
AbsorptionGastrointestinal absorption is uniform, rapid, and essentially complete.
Volume of distribution
  • 11 L
Protein binding98-99%, primarily to albumin.
Metabolism

Hepatic. The major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite which accounts for less than 2% of a dose, an acetylaminoethyl benzine derivatives, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound.

SubstrateEnzymesProduct
Glipizide
    3-cis-HydroxyglipizideDetails
    Glipizide
    4-trans-HydroxyglipizideDetails
    Route of eliminationThe primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine.
    Half life2-5 hours
    ClearanceNot Available
    ToxicityThe acute oral toxicity was extremely low in all species tested (LD50 greater than 4 g/kg). Overdosage of sulfonylureas including glipizide can produce hypoglycemia.
    Affected organisms
    • Humans and other mammals
    PathwaysNot Available
    SNP Mediated Effects
    Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
    Cytochrome P450 2C9
    Gene symbol: CYP2C9
    UniProt: P11712
    rs1057910 CYP2C9*1C AllelePoor drug metabolizer, lower dose requirements10208645
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.9262
    Blood Brain Barrier + 0.5599
    Caco-2 permeable - 0.7025
    P-glycoprotein substrate Substrate 0.5326
    P-glycoprotein inhibitor I Non-inhibitor 0.7469
    P-glycoprotein inhibitor II Non-inhibitor 0.9302
    Renal organic cation transporter Non-inhibitor 0.8322
    CYP450 2C9 substrate Substrate 0.5731
    CYP450 2D6 substrate Non-substrate 0.9116
    CYP450 3A4 substrate Non-substrate 0.719
    CYP450 1A2 substrate Non-inhibitor 0.9501
    CYP450 2C9 substrate Inhibitor 0.8949
    CYP450 2D6 substrate Non-inhibitor 0.9231
    CYP450 2C19 substrate Non-inhibitor 0.9025
    CYP450 3A4 substrate Non-inhibitor 0.8309
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8682
    Ames test Non AMES toxic 0.7745
    Carcinogenicity Non-carcinogens 0.826
    Biodegradation Not ready biodegradable 0.9703
    Rat acute toxicity 2.1662 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.9118
    hERG inhibition (predictor II) Non-inhibitor 0.8539
    Pharmacoeconomics
    Manufacturers
    • Watson laboratories inc
    • Pfizer inc
    • Alphapharm party ltd
    • Apotex inc
    • Caraco pharmaceutical laboratories ltd
    • Endo pharmaceuticals inc
    • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
    • Mylan pharmaceuticals inc
    • Par pharmaceutical inc
    • Pliva inc
    • Sandoz inc
    • Teva pharmaceuticals usa inc
    Packagers
    Dosage forms
    FormRouteStrength
    TabletOral
    Tablet, extended releaseOral
    Prices
    Unit descriptionCostUnit
    Glipizide powder36.11USDg
    Glucotrol XL 10 mg 24 Hour tablet1.53USDtablet
    Glucotrol xl 10 mg tablet1.37USDtablet
    Metaglip 5-500 mg tablet1.33USDtablet
    Metaglip 2.5-500 mg tablet1.32USDtablet
    Metaglip 2.5-250 mg tablet1.2USDtablet
    Glucotrol 10 mg tablet1.19USDtablet
    Glucotrol XL 2.5 mg 24 Hour tablet0.99USDtablet
    Glucotrol XL 5 mg 24 Hour tablet0.99USDtablet
    GlipiZIDE XL 10 mg 24 Hour tablet0.84USDtablet
    Glucotrol 5 mg tablet0.69USDtablet
    Glucotrol xl 2.5 mg tablet0.69USDtablet
    Glucotrol xl 5 mg tablet0.69USDtablet
    Glipizide 10 mg tablet0.67USDtablet
    GlipiZIDE XL 2.5 mg 24 Hour tablet0.63USDtablet
    GlipiZIDE XL 5 mg 24 Hour tablet0.5USDtablet
    Glipizide 5 mg tablet0.36USDtablet
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    United States55914541994-01-072014-01-07
    United States50248431992-09-052009-09-05
    Canada20245021997-11-112010-08-31
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point208-209 °CNot Available
    water solubility37.2 mg/LNot Available
    logP1.91HANSCH,C ET AL. (1995)
    pKa5.9PANTEN,U ET AL. (1989)
    Predicted Properties
    PropertyValueSource
    water solubility1.64e-02 g/lALOGPS
    logP1.83ALOGPS
    logP1.43ChemAxon
    logS-4.4ALOGPS
    pKa (strongest acidic)4.32ChemAxon
    pKa (strongest basic)0.059ChemAxon
    physiological charge-1ChemAxon
    hydrogen acceptor count6ChemAxon
    hydrogen donor count3ChemAxon
    polar surface area130.15ChemAxon
    rotatable bond count6ChemAxon
    refractivity115.62ChemAxon
    polarizability47.64ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleYesChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    Suresh Kumar Gidwani, Purushottam Singnurkar, Prashant Kumar Tewari, “Sustained release pharmaceutical composition containing glipizide and method for producing same.” U.S. Patent US6270797, issued February, 2000.

    US6270797
    General ReferenceNot Available
    External Links
    ResourceLink
    KEGG DrugD00335
    PubChem Compound3478
    PubChem Substance46505865
    ChemSpider3359
    BindingDB50012956
    Therapeutic Targets DatabaseDAP000920
    PharmGKBPA449762
    RxListhttp://www.rxlist.com/cgi/generic/glip.htm
    Drugs.comhttp://www.drugs.com/glipizide.html
    PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/cx1655.shtml
    WikipediaGlipizide
    ATC CodesA10BB07
    AHFS CodesNot Available
    PDB EntriesNot Available
    FDA labelshow(48.8 KB)
    MSDSshow(73.6 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, glipizide.
    AtenololThe beta-blocker, atenolol, may decrease symptoms of hypoglycemia.
    BisoprololThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
    CarvedilolThe beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.
    ChloramphenicolChloramphenicol may increase the effect of sulfonylurea, glipizide.
    ClofibrateClofibrate may increase the effect of sulfonylurea, glipizide.
    CyclosporineThe sulfonylurea, glipizide, may increase the effect of cyclosporine.
    EsmololThe beta-blocker, esmolol, may decrease symptoms of hypoglycemia.
    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.
    PhenylbutazonePhenylbutazone increases the effect of the hypoglycemic agent
    PindololThe beta-blocker, pindolol, may decrease symptoms of hypoglycemia.
    PropranololThe beta-blocker, propranolol, may decrease symptoms of hypoglycemia.
    RifampicinRifampin may decrease the effect of sulfonylurea, glipizide.
    Somatropin recombinantSomatropin may antagonize the hypoglycemic effect of glipizide. Monitor for changes in fasting and postprandial blood sugars.
    TimololThe beta-blocker, timolol, may decrease symptoms of hypoglycemia.
    TolbutamideTolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Glipizide. Consider alternate therapy or monitor for changes in Glipizide therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
    Food Interactions
    • Avoid alcohol.
    • Avoid sugar and sugary food.
    • Take 30-60 minutes before breakfast.

    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. 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. 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

    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. 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

    Comments
    Drug created on June 13, 2005 07:24 / Updated on January 11, 2014 08:47