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Identification
NameAcetohexamide
Accession NumberDB00414  (APRD00773)
Typesmall molecule
Groupswithdrawn
Description

A sulfonylurea hypoglycemic agent that is metabolized in the liver to 1-hydrohexamide. Acetohexamide has been discontinued in the US market.

Structure
Thumb
Synonyms
SynonymLanguageCode
1-((p-Acetylphenyl)sulfonyl)-3-cyclohexylureaNot AvailableNot Available
1-[(4-acetylbenzene)sulfonyl]-3-cyclohexylurea 4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamideNot AvailableIUPAC
AcetohexamidGermanINN
AcetohexamidaSpanishINN
AcétohexamideFrenchDCF
AcetohexamideNot AvailableBAN, JAN, USAN
AcetohexamidumLatinINN
N-(p-Acetylphenylsulfonyl)-N'-cyclohexylureaNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AcetohexamideWatson
DimelinShionogi Seiyaku
DymelorLilly
GamadiabetSalvat
Brand mixturesNot Available
Categories
CAS number968-81-0
WeightAverage: 324.395
Monoisotopic: 324.114377828
Chemical FormulaC15H20N2O4S
InChI KeyInChIKey=VGZSUPCWNCWDAN-UHFFFAOYSA-N
InChI
InChI=1S/C15H20N2O4S/c1-11(18)12-7-9-14(10-8-12)22(20,21)17-15(19)16-13-5-3-2-4-6-13/h7-10,13H,2-6H2,1H3,(H2,16,17,19)
IUPAC Name
1-[(4-acetylbenzene)sulfonyl]-3-cyclohexylurea
SMILES
CC(=O)C1=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 parentsAcetophenones; Benzoyl Derivatives; Sulfonylureas; Sulfonamides; Sulfonyls; Ketones; Enolates; Polyamines
Substituentsbenzoyl; sulfonylurea; sulfonic acid derivative; sulfonamide; sulfonyl; ketone; enolate; polyamine; amine; carbonyl group; 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
IndicationUsed in the management of diabetes mellitus type 2 (adult-onset).
PharmacodynamicsAcetohexamide is an intermediate-acting, first-generation oral sulfonylurea. It lowers blood sugar by stimulating the pancreatic beta cells to secrete insulin and by helping the body use insulin efficiently. The pancreas must produce insulin for this medication to work. Acetohexamide has one-third the potency of chlorpropamide, and twice the potency of tolbutamide; however, similar hypoglycemic efficacy occurs with equipotent dosage of sulfonylureas.
Mechanism of actionSulfonylureas such as acetohexamide bind to an ATP-dependent K+ channel on the cell membrane of pancreatic beta cells. This inhibits a tonic, hyperpolarizing outflux of potassium, which causes the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca2+ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin.
AbsorptionRapidly absorbed from the GI tract.
Volume of distributionNot Available
Protein binding90%
Metabolism

Extensively metabolized in the liver to the active metabolite hydroxyhexamide, which exhibits greater hypoglycemic potency than acetohexamide. Hydroxyhexamide is believed to be responsible for prolonged hypoglycemic effects.

SubstrateEnzymesProduct
Acetohexamide
    HydroxyhexamideDetails
    Route of eliminationNot Available
    Half lifeElimination half-life of the parent compound is 1.3 hours and the elimination half-life of the active metabolite is approximately 5-6 hours.
    ClearanceNot Available
    ToxicityOral, rat LD50: 5 gm/kg; Oral, mouse LD50: >2500 mg/kg. Symptoms of an acetohexamide overdose include hunger, nausea, anxiety, cold sweats, weakness, drowsiness, unconsciousness, and coma.
    Affected organisms
    • Humans and other mammals
    PathwaysNot Available
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.9425
    Blood Brain Barrier + 0.8308
    Caco-2 permeable - 0.6272
    P-glycoprotein substrate Non-substrate 0.6406
    P-glycoprotein inhibitor I Non-inhibitor 0.8731
    P-glycoprotein inhibitor II Non-inhibitor 0.8808
    Renal organic cation transporter Non-inhibitor 0.8538
    CYP450 2C9 substrate Substrate 0.6473
    CYP450 2D6 substrate Non-substrate 0.8795
    CYP450 3A4 substrate Non-substrate 0.7171
    CYP450 1A2 substrate Non-inhibitor 0.9045
    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 0.8309
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5913
    Ames test Non AMES toxic 0.9133
    Carcinogenicity Non-carcinogens 0.8447
    Biodegradation Not ready biodegradable 0.8033
    Rat acute toxicity 2.1793 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.8799
    hERG inhibition (predictor II) Non-inhibitor 0.8982
    Pharmacoeconomics
    Manufacturers
    • Barr laboratories inc
    • Usl pharma inc
    • Watson laboratories inc
    • Eli lilly industries inc
    Packagers
    Dosage formsNot Available
    PricesNot Available
    PatentsNot Available
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point188-190 °CSigal,M.V.,Jr.andVanArendonk,A.M.; US.Patent3,320,312;May16,1967;assigned to Eli Lilly and Company.
    water solubility3430 mg/L (at 37 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
    logP2.44SANGSTER (1993)
    logS-2.06ADME Research, USCD
    Predicted Properties
    PropertyValueSource
    water solubility4.83e-02 g/lALOGPS
    logP1.72ALOGPS
    logP1.81ChemAxon
    logS-3.8ALOGPS
    pKa (strongest acidic)4.31ChemAxon
    pKa (strongest basic)-7.4ChemAxon
    physiological charge-1ChemAxon
    hydrogen acceptor count4ChemAxon
    hydrogen donor count2ChemAxon
    polar surface area92.34ChemAxon
    rotatable bond count3ChemAxon
    refractivity82.77ChemAxon
    polarizability33.97ChemAxon
    number of rings2ChemAxon
    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 DrugD00219
    KEGG CompoundC06806
    PubChem Compound1989
    PubChem Substance46505821
    ChemSpider1912
    ChEBI28052
    ChEMBLCHEMBL1589
    Therapeutic Targets DatabaseDAP000922
    PharmGKBPA164777011
    Drug Product Database15598
    Drugs.comhttp://www.drugs.com/mtm/acetohexamide.html
    WikipediaAcetohexamide
    ATC CodesA10BB31
    AHFS CodesNot Available
    PDB EntriesNot Available
    FDA labelNot Available
    MSDSNot Available
    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 sulfonylurea, acetohexamide.
    AtenololThe beta-blocker, atenolol, may decrease symptoms of hypoglycemia.
    BetaxololThe beta-blocker, betaxolol, 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.
    ChloramphenicolChloramphenicol may increase the effect of sulfonylurea, acetohexamide.
    ClofibrateClofibrate may increase the effect of sulfonylurea, acetohexamide.
    DicoumarolDicumarol may increase the effect of sulfonylurea, acetohexamide.
    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 may increase the effect of acetohexamide.
    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, acetohexamide.
    SotalolThe beta-blocker, sotalol, may decrease symptoms of hypoglycemia.
    TimololThe beta-blocker, timolol, may decrease symptoms of hypoglycemia.
    Food Interactions
    • Avoid alcohol.
    • Take without regard to meals.

    1. ATP-sensitive inward rectifier potassium channel 1

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: inhibitor

    Components

    Name UniProt ID Details
    ATP-sensitive inward rectifier potassium channel 1 P48048 Details

    References:

    1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
    2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

    1. Carbonyl reductase [NADPH] 1

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Carbonyl reductase [NADPH] 1 P16152 Details

    References:

    1. Imamura Y, Shimada H: Differential pharmacokinetics of acetohexamide in male Wistar-Imamichi and Sprague-Dawley rats: role of microsomal carbonyl reductase. Biol Pharm Bull. 2005 Jan;28(1):185-7. Pubmed
    2. Imamura Y, Koga T, Higuchi T, Otagiri M, Sugino E, Hibino S: Inhibitory effect of drugs with a ketone group on reduction of acetohexamide catalyzed by carbonyl reductase from rabbit kidney. J Enzyme Inhib. 1997 Feb;11(4):285-92. Pubmed
    3. Kishimoto M, Kawamori R, Kamada T, Inaba T: Carbonyl reductase activity for acetohexamide in human erythrocytes. Drug Metab Dispos. 1994 May-Jun;22(3):367-70. Pubmed

    Comments
    Drug created on June 13, 2005 07:24 / Updated on March 12, 2014 11:52