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Identification
NameDicoumarol
Accession NumberDB00266  (APRD00761)
Typesmall molecule
Groupsapproved
Description

An oral anticoagulant that interferes with the metabolism of vitamin K. It is also used in biochemical experiments as an inhibitor of reductases. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
bis-3,3'-(4-hydroxycoumarinyl)methaneNot AvailableNot Available
bis-hydroxycoumarinNot AvailableNot Available
di-(4-hydroxy-3-coumarinyl)methaneNot AvailableNot Available
DicumarolNot AvailableUSAN
SaltsNot Available
Brand namesNot Available
Brand mixturesNot Available
Categories
CAS number66-76-2
WeightAverage: 336.295
Monoisotopic: 336.063388116
Chemical FormulaC19H12O6
InChI KeyDOBMPNYZJYQDGZ-UHFFFAOYSA-N
InChI
InChI=1S/C19H12O6/c20-16-10-5-1-3-7-14(10)24-18(22)12(16)9-13-17(21)11-6-2-4-8-15(11)25-19(13)23/h1-8,20-21H,9H2
IUPAC Name
4-hydroxy-3-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2H-chromen-2-one
SMILES
OC1=C(CC2=C(O)C3=C(OC2=O)C=CC=C3)C(=O)OC2=C1C=CC=C2
Mass Specshow(9.73 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassCoumarins and Derivatives
SubclassNot Available
Direct parentCoumarins and Derivatives
Alternative parentsBenzopyrans; Pyranones and Derivatives; Benzene and Substituted Derivatives; Polyamines
Substituentspyranone; benzene; pyran; polyamine
Classification descriptionThis compound belongs to the coumarins and derivatives. These are polycyclic aromatic compounds containing a 1-benzopyran moiety with a ketone group at the C2 carbon atom (1-benzopyran-2-one).
Pharmacology
IndicationFor decreasing blood clotting. Often used along with heparin for treatment of deep vein thrombosis.
PharmacodynamicsDicumarol is an coumarin-like compound found in sweet clover. It is used as an oral anticoagulant and acts by inhibiting the hepatic synthesis of vitamin K-dependent coagulation factors (prothrombin and factors VII, IX, and X). It is also used in biochemical experiments as an inhibitor of reductases.
Mechanism of actionDicumarol inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decresed prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityLD50=233 mg/kg (orally in mice); LD50=250 mg/kg (orally in rats)
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Dicumarol Action PathwayDrug actionSMP00270
Dicoumarol Action PathwayDrug actionSMP00656
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.8724
Blood Brain Barrier + 0.8343
Caco-2 permeable - 0.5899
P-glycoprotein substrate Non-substrate 0.5073
P-glycoprotein inhibitor I Non-inhibitor 0.9304
P-glycoprotein inhibitor II Non-inhibitor 0.8972
Renal organic cation transporter Non-inhibitor 0.8982
CYP450 2C9 substrate Non-substrate 0.8264
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.7557
CYP450 1A2 substrate Non-inhibitor 0.7905
CYP450 2C9 substrate Inhibitor 0.8948
CYP450 2D6 substrate Non-inhibitor 0.9681
CYP450 2C19 substrate Non-inhibitor 0.6071
CYP450 3A4 substrate Non-inhibitor 0.9098
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9165
Ames test Non AMES toxic 0.9048
Carcinogenicity Non-carcinogens 0.9549
Biodegradation Not ready biodegradable 0.8347
Rat acute toxicity 3.1251 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9269
hERG inhibition (predictor II) Non-inhibitor 0.9435
Pharmacoeconomics
Manufacturers
  • Eli lilly and co
  • Abbott laboratories pharmaceutical products div
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point290 °CPhysProp
water solubility128 mg/LNot Available
logP2.07HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
water solubility6.62e-02 g/lALOGPS
logP1.54ALOGPS
logP-1.6ChemAxon
logS-3.7ALOGPS
pKa (strongest acidic)-12ChemAxon
pKa (strongest basic)-3.1ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count2ChemAxon
polar surface area93.06ChemAxon
rotatable bond count2ChemAxon
refractivity89.19ChemAxon
polarizability32.32ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Cullen JJ, Hinkhouse MM, Grady M, Gaut AW, Liu J, Zhang YP, Weydert CJ, Domann FE, Oberley LW: Dicumarol inhibition of NADPH:quinone oxidoreductase induces growth inhibition of pancreatic cancer via a superoxide-mediated mechanism. Cancer Res. 2003 Sep 1;63(17):5513-20. Pubmed
  2. Mironov AA, Colanzi A, Polishchuk RS, Beznoussenko GV, Mironov AA Jr, Fusella A, Di Tullio G, Silletta MG, Corda D, De Matteis MA, Luini A: Dicumarol, an inhibitor of ADP-ribosylation of CtBP3/BARS, fragments golgi non-compact tubular zones and inhibits intra-golgi transport. Eur J Cell Biol. 2004 Jul;83(6):263-79. Pubmed
  3. Abdelmohsen K, Stuhlmann D, Daubrawa F, Klotz LO: Dicumarol is a potent reversible inhibitor of gap junctional intercellular communication. Arch Biochem Biophys. 2005 Feb 15;434(2):241-7. Pubmed
  4. Thanos CG, Liu Z, Reineke J, Edwards E, Mathiowitz E: Improving relative bioavailability of dicumarol by reducing particle size and adding the adhesive poly(fumaric-co-sebacic) anhydride. Pharm Res. 2003 Jul;20(7):1093-100. Pubmed
External Links
ResourceLink
KEGG DrugD03798
KEGG CompoundC00796
BindingDB35525
ChEBI4513
ChEMBLCHEMBL1466
Therapeutic Targets DatabaseDAP000768
PharmGKBPA449298
WikipediaDicumarol
ATC CodesB01AA01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(64.7 KB)
Interactions
Drug Interactions
Drug
AcetaminophenAcetaminophen may increase the anticoagulant effect of dicumarol. Monitor for changes in the therapeutic and adverse effects of dicumarol if acetaminophen is initiated, discontinued or dose changed.
AcetohexamideDicumarol may increase the effect of sulfonylurea, acetohexamide.
Acetylsalicylic acidAcetylsalicylic acid increases effect of the anticoagulant, dicumarol.
AllopurinolAllopurinol may increase the anticoagulant effect of dicumarol.
AminoglutethimideAminoglutethimide may decrease the anticoagulant effect of dicumarol.
AmiodaroneAmiodarone may increase the anticoagulant effect of dicumarol.
AmprenavirAmprenavir may increase the anticoagulant effect of dicumarol by increasing its serum concentration.
AprepitantAprepitant may decrease the anticoagulant effect of dicumarol by decreasing its serum concentration.
AtazanavirThe protease inhibitor, atazanavir, may increase the anticoagulant effect of dicumarol.
AzathioprineAzathioprine may decrease the anticoagulant effect of dicumarol.
AzithromycinAzithromycin may increase the anticoagulant effect of dicumarol by increasing its serum concentration.
BetamethasoneThe corticosteroid, betamethasone, alters the anticoagulant effect of dicumarol.
BosentanBosentan may decrease the anticoagulant effect of dicumarol by increasing its metabolism.
CapecitabineCapecitabine may increase the anticoagulant effect of dicumarol by increasing its serum concentration.
CarbamazepineCarbamazepine may decrease the anticoagulant effect of dicumarol by decreasing its serum concentration.
CefotetanThe cephalosporin, cefotetan, may increase the anticoagulant effect of dicumarol.
CefoxitinThe cephalosporin, cefoxitin, may increase the anticoagulant effect of dicumarol.
CeftriaxoneThe cephalosporin, ceftriaxone, may increase the anticoagulant effect of dicumarol.
CelecoxibCelecoxib may increase the anticoagulant effect of dicumarol.
ChlorpropamideDicumarol may increase the effect of sulfonylurea, chlorpropamide.
CholestyramineThe bile acid sequestrant, cholestyramine, may decrease the anticoagulant effect of dicumarol by decreasing its absorption.
CimetidineCimetidine may increase the anticoagulant effect of dicumarol.
CiprofloxacinThe quinolone antibiotic, ciprofloxacin, may increase the anticoagulant effect of dicumarol.
CisaprideCisapride may increase the anticoagulant effect of dicumarol.
CitalopramThe SSRI, citalopram, increases the effect of anticoagulant, dicumarol.
ClarithromycinThe macrolide, clarithromycin, may increase the anticoagulant effect of dicumarol.
ClofibrateThe fibrate increases the anticoagulant effect
ColestipolThe bile acid sequestrant, colestipol, may decrease the anticoagulant effect of dicumarol by decreasing its absorption.
CyclophosphamideThe antineoplastic agent, cyclophosphamide may alter the anticoagulant effect of dicumarol.
DanazolThe androgen, danazol, may increase the anticoagulant effect of dicumarol.
DemeclocyclineThe tetracycline, demeclocycline, may increase the anticoagulant effect of dicumarol.
DexamethasoneThe corticosteroid, dexamethasone, alters the anticoagulant effect of dicumarol.
DextropropoxyphenePropoxyphene may increase the anticoagulant effect of dicumarol.
DextrothyroxineThe thyroid hormone, dextrothyroxine, increase the anticoagulant effect of dicumarol.
DiclofenacThe NSAID, diclofenac, may increase the anticoagulant effect of dicumarol.
DicloxacillinDicloxacillin may decrease the anticoagulant effect of dicumarol.
DiflunisalThe NSAID, diflunisal, may increase the anticoagulant effect of dicumarol.
DisulfiramDisulfiram may increase the anticoagulant effect of dicumarol.
DoxycyclineThe tetracycline, doxycycline, may increase the anticoagulant effect of dicumarol.
ErythromycinThe macrolide, erythromycin, may increase the anticoagulant effect of dicumarol..
EthchlorvynolEthchlorvynol may decrease the anticoagulant effect of dicumarol.
Ethinyl EstradiolIncreased thrombotic risk due to estrogen
EtodolacThe NSAID, etodolac, may increase the anticoagulant effect of dicumarol.
EtoricoxibEtoricoxib may increase the anticoagulant effect of dicumarol.
FenofibrateFenofibrate may increase the anticoagulant effect of dicumarol.
FenoprofenThe NSAID, fenoprofen, may increase the anticoagulant effect of dicumarol.
FluconazoleFluconazole may increase the serum concentration of dicumarol by decreasing its metabolism.
FludrocortisoneThe corticosteroid, fludrocortisone, alters the anticoagulant effect of dicumarol.
FluorouracilThe antineoplasic agent, fluorouracil, may increase the anticoagulant effect of dicumarol.
FluoxetineThe SSRI, fluoxetine, increases the effect of anticoagulant, dicumarol.
FluoxymesteroneThe androgen, fluoxymesterone, may increase the anticoagulant effect of dicumarol.
FlurbiprofenThe NSAID, flurbiprofen, may increase the anticoagulant effect of dicumarol.
FluvastatinFluvastatin may increase the anticoagulant effect of dicumarol. Monitor for changes in the therapeutic and adverse effects of dicumarol if fluvastatin if initiated, discontinued or dose changed.
FluvoxamineFluvoxamine may increase the anticoagulant effect of dicumarol by increasing its serum concentration.
FosamprenavirThe protease inhibitor, fosamprenavir, may increase the anticoagulant effect of dicumarol.
FosphenytoinIncreased hydantoin levels and risk of bleeding
GefitinibGefitinib may increase the anticoagulant effect of dicumarol.
GemcitabineGemcitabine may increase the anticoagulant effect of dicumarol.
GemfibrozilGemfibrozil may increase the anticoagulant effect of dicumarol.
GliclazideDicumarol may increase the effect of sulfonylurea, gliclazide.
GlutethimideGlutethimide may decrease the anticoagulant effect of dicumarol.
GlyburideDicumarol may increase the effect of sulfonylurea, glibenclamide.
GriseofulvinGriseofulvin may decrease the anticoagulant effect of dicumarol.
HydrocortisoneThe corticosteroid, hydrocortisone, alters the anticoagulant effect of dicumarol.
IbuprofenThe NSAID, ibuprofen, may increase the anticoagulant effect of dicumarol.
ImatinibImatinib may increase the anticoagulant effect of dicumarol.
IndinavirThe protease inhibitor, indinavir, may increase the anticoagulant effect of dicumarol.
IndomethacinThe NSAID, indomethacin, may increase the anticoagulant effect of dicumarol.
IsoniazidIsoniazid may increase the anticoagulant effect of dicumarol.
ItraconazoleItraconazole may increase the anticoagulant effect of dicumarol.
KetoconazoleKetoconazole may increase the anticoagulant effect of dicumarol.
KetoprofenThe NSAID, ketoprofen, may increase the anticoagulant effect of dicumarol.
KetorolacThe NSAID, ketorolac, may increase the anticoagulant effect of dicumarol.
LeflunomideLeflunomide may increase the anticoagulant effect of dicumarol.
LevamisoleLevamisole may increase the anticoagulant effect of dicumarol.
LevofloxacinThe quinolone antibiotic, levofloxacin, may increase the anticoagulant effect of dicumarol.
LevothyroxineThe thyroid hormone, levothyroxine, increase the anticoagulant effect of dicumarol.
LovastatinLovastatin may increase the anticoagulant effect dicumarol. Monitor for changes in the therapeutic and adverse effects of dicumarol if lovastatin is initiated, discontinued or dose changed.
LumiracoxibLumiracoxib may increase the anticoagulant effect of dicumarol.
Medroxyprogesterone AcetateMedroxyprogesterone may increase the anticoagulant effect of dicumarol.
Mefenamic acidThe NSAID, mefanamic acid, may increase the anticoagulant effect of dicumarol.
MefloquineMefloquine may increase the anticoagulant effect of dicumarol.
MeloxicamMeloxicam may increase the anticoagulant effect of dicumarol.
MercaptopurineMercaptopurine may decrease the anticoagulant effect of dicumarol.
MethimazoleThe antithyroid agent, methimazole, may decrease the anticoagulant effect of dicumarol.
MetronidazoleMetronidazole may increase the anticoagulant effect of dicumarol.
MiconazoleMiconazole may increase the serum concentration of dicumarol by decreasing its metabolism.
MinocyclineThe tetracycline, minocycline, may increase the anticoagulant effect of dicumarol.
MitotaneMitotane may decrease the anticoagulant effect of dicumarol.
MoxifloxacinThe quinolone antibiotic, moxifloxacin, may increase the anticoagulant effect of dicumarol.
NabumetoneThe NSAID, nabumetone, may increase the anticoagulant effect of dicumarol.
Nalidixic AcidThe quinolone antibiotic, nalidixic acid, may increase the anticoagulant effect of dicumarol.
NaproxenThe NSAID, naproxen, may increase the anticoagulant effect of dicumarol.
NelfinavirThe protease inhibitor, nelfinavir, may increase the anticoagulant effect of dicumarol.
NevirapineNevirapine may decrease the anticoagulant effect of dicumarol.
NorfloxacinThe quinolone antibiotic, norfloxacin, may increase the anticoagulant effect of dicumarol.
OfloxacinThe quinolone antibiotic, ofloxacin, may increase the anticoagulant effect of dicumarol.
OrlistatOrlistat may increase the anticoagulant effect of dicumarol.
OxaprozinThe NSAID, oxaprozin, may increase the anticoagulant effect of dicumarol.
OxyphenbutazoneThe NSAID, oxyphenbutazone, may increase the anticoagulant effect of dicumarol.
ParoxetineThe SSRI, paroxetine, increases the effect of anticoagulant, dicumarol.
PentoxifyllinePentoxifylline may increase the anticoagulant effect of dicumarol.
PhenobarbitalThe barbiturate, phenobarbital, decreases the anticoagulant effect, dicumarol.
PhenylbutazoneThe NSAID, phenylbutazone, may increase the anticoagulant effect of dicumarol.
PhenytoinIncreased hydantoin levels and risk of bleeding
PiroxicamThe NSAID, piroxicam, may increase the anticoagulant effect of dicumarol.
PrednisoloneThe corticosteroid, prednisolone, alters the anticoagulant effect of dicumarol.
PrednisoneThe corticosteroid, prednisone, alters the anticoagulant effect of dicumarol.
PrimidoneThe barbiturate, primidone, decreases the anticoagulant effect, dicumarol.
PropafenonePropafenone may increase the anticoagulant effect of dicumarol.
PropylthiouracilThe anti-thyroid agent, propylthiouracil, may decrease the anticoagulant effect of dicumarol.
QuinidineQuinidine may increase the anticoagulant effect of dicumarol.
QuinineQuinine may increase the anticoagulant effect of dicumarol.
RanitidineRanitidine may increase the anticoagulant effect of dicumarol. (Conflicting evidence)
RifabutinRifabutin may decrease the anticoagulant effect of dicumarol.
RifampicinRifampin may decrease the anticoagulant effect of dicumarol.
TelithromycinTelithromycin may increase the anticoagulant effect of dicumarol.
TenoxicamThe NSAID, tenoxicam, may increase the anticoagulant effect of dicumarol.
TestosteroneThe androgen may increase the anticoagulant effect of dicumarol.
TetracyclineTetracycline may increase the anticoagulant effect of dicumarol.
TigecyclineTigecycline may increase the anticoagulant effect of dicumarol.
TriamcinoloneThe corticosteroid, triamcinolone, alters the anticoagulant effect of dicumarol.
Food InteractionsNot Available

Targets

1. Vitamin K epoxide reductase complex subunit 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Vitamin K epoxide reductase complex subunit 1 Q9BQB6 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
  3. Wallin R, Patrick SD, Ballard JO: Vitamin K antagonism of coumarin intoxication in the rat. Thromb Haemost. 1986 Apr 30;55(2):235-9. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. NAD(P)H dehydrogenase [quinone] 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
NAD(P)H dehydrogenase [quinone] 1 P15559 Details

References:

  1. Chen S, Wu K, Zhang D, Sherman M, Knox R, Yang CS: Molecular characterization of binding of substrates and inhibitors to DT-diaphorase: combined approach involving site-directed mutagenesis, inhibitor-binding analysis, and computer modeling. Mol Pharmacol. 1999 Aug;56(2):272-8. Pubmed
  2. Jaiswal AK: Characterization and partial purification of microsomal NADH:quinone oxidoreductases. Arch Biochem Biophys. 2000 Mar 1;375(1):62-8. Pubmed
  3. Joseph P, Jaiswal AK: A unique cytosolic activity related but distinct from NQO1 catalyses metabolic activation of mitomycin C. Br J Cancer. 2000 Apr;82(7):1305-11. Pubmed
  4. Floreani M, Napoli E, Palatini P: Protective action of cardiac DT-diaphorase against menadione toxicity in guinea pig isolated atria. Biochem Pharmacol. 2000 Aug 15;60(4):601-5. Pubmed
  5. Arriagada C, Dagnino-Subiabre A, Caviedes P, Armero JM, Caviedes R, Segura-Aguilar J: Studies of aminochrome toxicity in a mouse derived neuronal cell line: is this toxicity mediated via glutamate transmission? Amino Acids. 2000;18(4):363-73. Pubmed
  6. Preusch PC, Smalley DM: Vitamin K1 2,3-epoxide and quinone reduction: mechanism and inhibition. Free Radic Res Commun. 1990;8(4-6):401-15. Pubmed

3. Quinone oxidoreductase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Quinone oxidoreductase Q08257 Details

References:

  1. Evans PJ: Decreased intracellular proteolysis correlates with the maintenance of a specific isoenzyme of cytochrome P-450. Cell Biol Int. 1999;23(2):117-24. Pubmed
  2. Audi SH, Bongard RD, Dawson CA, Siegel D, Roerig DL, Merker MP: Duroquinone reduction during passage through the pulmonary circulation. Am J Physiol Lung Cell Mol Physiol. 2003 Nov;285(5):L1116-31. Epub 2003 Jul 25. Pubmed
  3. Asher G, Dym O, Tsvetkov P, Adler J, Shaul Y: The crystal structure of NADH quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol. Biochemistry. 2006 May 23;45(20):6372-8. Pubmed
  4. Maser E, Gebel T, Netter KJ: Carbonyl reduction of metyrapone in human liver. Biochem Pharmacol. 1991 Dec 11;42 Suppl:S93-8. Pubmed
  5. Hao H, Wang G, Cui N, Li J, Xie L, Ding Z: Identification of a novel intestinal first pass metabolic pathway: NQO1 mediated quinone reduction and subsequent glucuronidation. Curr Drug Metab. 2007 Feb;8(2):137-49. Pubmed

Enzymes

1. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate 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

Comments
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Drug created on June 13, 2005 07:24 / Updated on September 25, 2013 16:59