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Identification
NameDisulfiram
Accession NumberDB00822  (APRD00767)
Typesmall molecule
Groupsapproved
Description

A carbamate derivative used as an alcohol deterrent. It is a relatively nontoxic substance when administered alone, but markedly alters the intermediary metabolism of alcohol. When alcohol is ingested after administration of disulfiram, blood acetaldehyde concentrations are increased, followed by flushing, systemic vasodilation, respiratory difficulties, nausea, hypotension, and other symptoms (acetaldehyde syndrome). It acts by inhibiting aldehyde dehydrogenase. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
1,1'-dithiobis(N,N-diethylthioformamide)Not AvailableNot Available
Antabuse (tn)Not AvailableNot Available
Bis(diethylthiocarbamoyl) disulfideNot AvailableNot Available
DisulfiramNot AvailableNot Available
N,N,N',N'-tetraethylthiuram disulfideNot AvailableNot Available
Tetraethylthioperoxydicarbonic DiamideNot AvailableNot Available
Tetraethylthiuram DisulfideNot AvailableNot Available
Tetraethylthiuram DisulphideNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AntabusActavis
AntabuseActavis
AntaethylSanofi
AntalcolSintofarm
AnticolPolfa Warszawa
AntietanolSanofi
ChronolCharoon Bhesaj
EsperalSanofi
Brand mixturesNot Available
Categories
CAS number97-77-8
WeightAverage: 296.539
Monoisotopic: 296.05093141
Chemical FormulaC10H20N2S4
InChI KeyAUZONCFQVSMFAP-UHFFFAOYSA-N
InChI
InChI=1S/C10H20N2S4/c1-5-11(6-2)9(13)15-16-10(14)12(7-3)8-4/h5-8H2,1-4H3
IUPAC Name
N,N-diethyl[(diethylcarbamothioyl)disulfanyl]carbothioamide
SMILES
CCN(CC)C(=S)SSC(=S)N(CC)CC
Mass Specshow(8.65 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassOrganosulfur Compounds
ClassThiocarbonyl Compounds
SubclassOrganic Thiocarbonic Acid Derivatives
Direct parentOrganic Thiocarbonic Acid Derivatives
Alternative parentsTertiary Amines; Organic Disulfides; Polyamines
Substituentspolyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the organic thiocarbonic acid derivatives. These are organic compounds containing the thiocarbonic acid structure or a derivative thereof.
Pharmacology
IndicationFor the treatment and management of chronic alcoholism
PharmacodynamicsDisulfiram produces a sensitivity to alcohol which results in a highly unpleasant reaction when the patient under treatment ingests even small amounts of alcohol. Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage during alcohol metabolism following disulfiram intake, the concentration of acetaldehyde occurring in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. Accumulation of acetaldehyde in the blood produces a complex of highly unpleasant symptoms referred to hereinafter as the disulfiram-alcohol reaction. This reaction, which is proportional to the dosage of both disulfiram and alcohol, will persist as long as alcohol is being metabolized. Disulfiram does not appear to influence the rate of alcohol elimination from the body. Prolonged administration of disulfiram does not produce tolerance; the longer a patient remains on therapy, the more exquisitely sensitive he becomes to alcohol.
Mechanism of actionDisulfiram blocks the oxidation of alcohol at the acetaldehyde stage during alcohol metabolism following disulfiram intake causing an accumulation of acetaldehyde in the blood producing highly unpleasant symptoms. Disulfiram blocks the oxidation of alcohol through its irreversible inactivation of aldehyde dehydrogenase, which acts in the second step of ethanol utilization. In addition, disulfiram competitively binds and inhibits the peripheral benzodiazepine receptor, which may indicate some value in the treatment of the symptoms of alcohol withdrawal, however this activity has not been extensively studied.
AbsorptionDisulfiram is absorbed slowly from the gastrointestinal tract (80 to 90% of oral dose).
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic.

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityLD50=8.6g/kg (orally in rats). Symptoms of overdose include irritation, slight drowsiness, unpleasant taste, mild GI disturbances, and orthostatic hypotension.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Disulfiram Action PathwayDrug actionSMP00429
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9808
Blood Brain Barrier + 0.9668
Caco-2 permeable + 0.548
P-glycoprotein substrate Non-substrate 0.71
P-glycoprotein inhibitor I Non-inhibitor 0.8236
P-glycoprotein inhibitor II Non-inhibitor 0.9884
Renal organic cation transporter Non-inhibitor 0.8379
CYP450 2C9 substrate Non-substrate 0.8497
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.7558
CYP450 1A2 substrate Inhibitor 0.9106
CYP450 2C9 substrate Inhibitor 0.8948
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Inhibitor 0.8994
CYP450 3A4 substrate Inhibitor 0.796
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5397
Ames test Non AMES toxic 0.9132
Carcinogenicity Carcinogens 0.6989
Biodegradation Not ready biodegradable 0.9767
Rat acute toxicity 2.7419 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8617
hERG inhibition (predictor II) Non-inhibitor 0.8823
Pharmacoeconomics
Manufacturers
  • Odyssey pharmaceuticals inc
  • Par pharmaceutical inc
  • Watson laboratories inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Antabuse 500 mg tablet6.65USDtablet
Antabuse 250 mg tablet4.24USDtablet
Disulfiram powder1.92USDg
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point71.5 °CPhysProp
boiling point117 °C at 1.70E+01 mm HgPhysProp
water solubility4.09 mg/L (at 25 °C)YALKOWSKY,SH & HE,Y (2003)
logP3.88HANSCH,C ET AL. (1995)
logS-4.86ADME Research, USCD
Predicted Properties
PropertyValueSource
water solubility1.26e-02 g/lALOGPS
logP3.88ALOGPS
logP4.16ChemAxon
logS-4.4ALOGPS
physiological charge0ChemAxon
hydrogen acceptor count0ChemAxon
hydrogen donor count0ChemAxon
polar surface area6.48ChemAxon
rotatable bond count7ChemAxon
refractivity88.24ChemAxon
polarizability31.6ChemAxon
number of rings0ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Adams, H.S. and Meuser, L.; US.Patent 1,782,111; November 18,1930; assigned to The
Naugatuck Chemical Company.
Bailey, G.C.; U.S.Patent 1,796,977; March 17,1931; assigned to The Roessler & Hasslacher
Chemical Company.

General Reference
  1. Nash T, Rice WG: Efficacies of zinc-finger-active drugs against Giardia lamblia. Antimicrob Agents Chemother. 1998 Jun;42(6):1488-92. Pubmed
  2. Bouma MJ, Snowdon D, Fairlamb AH, Ackers JP: Activity of disulfiram (bis(diethylthiocarbamoyl)disulphide) and ditiocarb (diethyldithiocarbamate) against metronidazole-sensitive and -resistant Trichomonas vaginalis and Tritrichomonas foetus. J Antimicrob Chemother. 1998 Dec;42(6):817-20. Pubmed
  3. Gaval-Cruz M, Weinshenker D: mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv. 2009 Aug;9(4):175-87. Pubmed 19720750
External Links
ResourceLink
KEGG DrugD00131
KEGG CompoundC01692
PubChem Compound3117
PubChem Substance46506008
ChemSpider3005
ChEBI4659
ChEMBLCHEMBL964
Therapeutic Targets DatabaseDAP000012
PharmGKBPA449376
Drug Product Database2534
RxListhttp://www.rxlist.com/cgi/generic/disulfiram.htm
Drugs.comhttp://www.drugs.com/cdi/disulfiram.html
WikipediaDisulfiram
ATC CodesN07BB01P03AA04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(50.6 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolDisulfiram may increase the anticoagulant effect of acenocoumarol.
AminophyllineDisulfiram may increase the effect and toxicity of aminophylline.
AmprenavirIncreased irsk of side effects (oral solution)
AnisindioneDisulfiram may increase the anticoagulant effect of anisindione.
ChlorzoxazoneDisulfiram may increase the serum level of chlorzoxazone by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of chlorzoxazone if diltiazem is initiated, discontinued or dose changed.
CocaineIncreases the cardiac toxicity of cocaine
DicoumarolDisulfiram may increase the anticoagulant effect of dicumarol.
DyphyllineIncreases the effect and toxicity of theophylline
EthotoinIncreases the effect of phenytoin
FosphenytoinDisulfiram may increase the effect of fosphenytoin.
IsoniazidIncreased risk of CNS adverse effects
MephenytoinIncreases the effect of phenytoin
MetronidazolePossible acute psychosis and confusion
OxtriphyllineDisulfiram may increase the effect and toxicity of oxtriphylline.
PhenytoinDisulfiram may increase the therapeutic and adverse effects of phenytoin.
TheophyllineDisulfiram may increase the effect and toxicity of theophylline.
TipranavirDisulfiram may cause Tipranavir (Aptivus brand) toxicity by inhibiting alcohol metabolism. Aptivus capsules contain alcohol.
TrimethadioneDisulfiram, a strong CYP2E1 inhibitor, may decrease the metabolism and clearance of Trimethadione, a CYP2E1 substrate. Consider alternate therapy or monitor for changes in Trimethadione therapeutic and adverse effects if Disulfiram is initiated, discontinued or dose changed.
WarfarinDisulfiram may increase the anticoagulant effect of warfarin.
Food Interactions
  • Avoid alcohol for up to 14 days after treatment has been stopped.
  • Take without regard to meals.

Targets

1. Aldehyde dehydrogenase, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Aldehyde dehydrogenase, mitochondrial P05091 Details

References:

  1. Mackenzie IS, Maki-Petaja KM, McEniery CM, Bao YP, Wallace SM, Cheriyan J, Monteith S, Brown MJ, Wilkinson IB: Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans. Arterioscler Thromb Vasc Biol. 2005 Sep;25(9):1891-5. Epub 2005 Jul 28. Pubmed
  2. Ho MP, Yo CH, Liu CM, Chen CL, Lee CC: Refractive hypotension in a patient with disulfiram-ethanol reaction. Am J Med Sci. 2007 Jan;333(1):53-5. Pubmed

2. Dopamine beta-hydroxylase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Dopamine beta-hydroxylase P09172 Details

References:

  1. Gaval-Cruz M, Weinshenker D: mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv. 2009 Aug;9(4):175-87. Pubmed *

Enzymes

1. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  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

2. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 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

3. 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

4. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 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

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Drug created on June 13, 2005 07:24 / Updated on April 15, 2014 12:31