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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
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
AcetohexamideWatson
DimelinShionogi Seiyaku
DymelorLilly
GamadiabetSalvat
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number968-81-0
WeightAverage: 324.395
Monoisotopic: 324.114377828
Chemical FormulaC15H20N2O4S
InChI KeyVGZSUPCWNCWDAN-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
3-(4-acetylbenzenesulfonyl)-1-cyclohexylurea
SMILES
CC(=O)C1=CC=C(C=C1)S(=O)(=O)NC(=O)NC1CCCCC1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as benzenesulfonamides. These are organic compounds containing a sulfonamide group that is S-linked to a benzene ring.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassBenzenesulfonamides
Direct ParentBenzenesulfonamides
Alternative Parents
Substituents
  • Benzenesulfonamide
  • Acetophenone
  • Aryl alkyl ketone
  • Aryl ketone
  • Benzoyl
  • Sulfonylurea
  • Cyclohexylamine
  • Aminosulfonyl compound
  • Sulfonyl
  • Sulfonic acid derivative
  • Sulfonamide
  • Ketone
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
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
Not Available
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
PropertyValueProbability
Human Intestinal Absorption+0.9425
Blood Brain Barrier+0.8308
Caco-2 permeable-0.6272
P-glycoprotein substrateNon-substrate0.6406
P-glycoprotein inhibitor INon-inhibitor0.8731
P-glycoprotein inhibitor IINon-inhibitor0.8808
Renal organic cation transporterNon-inhibitor0.8538
CYP450 2C9 substrateSubstrate0.6473
CYP450 2D6 substrateNon-substrate0.8795
CYP450 3A4 substrateNon-substrate0.7171
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 substrateNon-inhibitor0.9071
CYP450 2D6 substrateNon-inhibitor0.9231
CYP450 2C19 substrateNon-inhibitor0.9025
CYP450 3A4 substrateNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5913
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.8447
BiodegradationNot ready biodegradable0.8033
Rat acute toxicity2.1793 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8799
hERG inhibition (predictor II)Non-inhibitor0.8982
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 Solubility0.0483 mg/mLALOGPS
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 Area92.34 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity82.77 m3·mol-1ChemAxon
Polarizability33.97 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ATC CodesNot Available
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.

Targets

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

Enzymes

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

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