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Identification
NameDacarbazine
Accession NumberDB00851  (APRD00331)
TypeSmall Molecule
GroupsApproved, Investigational
Description

An antineoplastic agent. It has significant activity against melanomas. (from Martindale, The Extra Pharmacopoeia, 31st ed, p564). Dacarbazine with Oblimersen is in clinical trials for the treatment of malignant melanoma.

Structure
Thumb
Synonyms
SynonymLanguageCode
4-(3,3-Dimethyl-1-triazeno)imidazole-5-carboxamideNot AvailableNot Available
4-(5)-(3,3-Dimethyl-1-triazeno)imidazole-5(4)-carboxamideNot AvailableNot Available
4-(Dimethyltriazeno)imidazole-5-carboxamideNot AvailableNot Available
5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamideNot AvailableNot Available
5-(3,3-Dimethyltriazeno)imidazole-4-carboxamideNot AvailableNot Available
5-(Dimethyltriazeno)imidazole-4-carboxamideNot AvailableNot Available
BiocarbazineNot AvailableIS
DacarbazinGermanINN
DacarbazinaSpanishINN
DacarbazineFrenchINN
DacarbazinumLatinINN
DICNot AvailableNot Available
DTCINot AvailableNot Available
Dtic-dome (tn)Not AvailableNot Available
DTIENot AvailableIS
HSDB 3219Not AvailableNot Available
ICDMTNot AvailableNot Available
Imidazole CarboxamideNot AvailableNot Available
Imidazole-4-carboxamide, 5-(3,3-dimethyl-1-triazeno)-Not AvailableNot Available
NCI-C04717Not AvailableNot Available
NSC 45388Not AvailableNot Available
NSC-45388Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
DacaticOrion Corporation
DéticèneSanofi-Aventis
DeticeneSanofi-Aventis
Detimedacmedac GmbH
DTICBayer AG
DTIC-DomeBayer Schering
Brand mixturesNot Available
Categories
CAS number4342-03-4
WeightAverage: 182.1832
Monoisotopic: 182.091608972
Chemical FormulaC6H10N6O
InChI KeyFDKXTQMXEQVLRF-UHFFFAOYSA-N
InChI
InChI=1S/C6H10N6O/c1-12(2)11-10-6-4(5(7)13)8-3-9-6/h3H,1-2H3,(H2,7,13)(H,8,9)
IUPAC Name
5-(dimethyltriaz-1-en-1-yl)-1H-imidazole-4-carboxamide
SMILES
CN(C)N=NC1=C(N=CN1)C(N)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzoles
SubclassImidazoles
Direct parentCarbonylimidazoles
Alternative parentsPrimary Carboxylic Acid Amides; Polyamines; Enolates; Carboxylic Acids
Substituentscarboxamide group; primary carboxylic acid amide; carboxylic acid derivative; polyamine; enolate; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the carbonylimidazoles. These are substituted imidazoles in which the imidazole ring bears a carbonyl group.
Pharmacology
IndicationFor the treatment of metastatic malignant melanoma. In addition, dacarbazine is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other antineoplastic agents.
PharmacodynamicsDacarbazine is a synthetic analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC). After intravenous administration of dacarbazine, the volume of distribution exceeds total body water content suggesting localization in some body tissue, probably the liver. Its disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours. 1 In a patient with renal and hepatic dysfunctions, the half-lives were lengthened to 55 minutes and 7.2 hours. 1 The average cumulative excretion of unchanged DTIC in the urine is 40% of the injected dose in 6 hours. 1 DTIC is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations dacarbazine is not appreciably bound to human plasma protein.
Mechanism of actionThe mechanism of action is not known, but appears to exert cytotoxic effects via its action as an alkylating agent. Other theories include DNA synthesis inhibition by its action as a purine analog, and interaction with SH groups. Dacarbazine is not cell cycle-phase specific.
AbsorptionErratic, slow and incomplete
Volume of distributionNot Available
Protein bindingLess than 5%
Metabolism

Hepatic

Route of eliminationDacarbazine is subject to renal tubular secretion rather than glomerular filtration. In man, dacarbazine is extensively degraded. Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine.
Half life5 hours
ClearanceNot Available
ToxicityLD50=350mg/kg (orally in mice)
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 + 0.9923
Blood Brain Barrier + 0.9382
Caco-2 permeable + 0.5278
P-glycoprotein substrate Non-substrate 0.6608
P-glycoprotein inhibitor I Non-inhibitor 0.8478
P-glycoprotein inhibitor II Non-inhibitor 0.9363
Renal organic cation transporter Non-inhibitor 0.9125
CYP450 2C9 substrate Non-substrate 0.7898
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.579
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9496
CYP450 2D6 substrate Non-inhibitor 0.9413
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.99
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8208
Ames test AMES toxic 0.9107
Carcinogenicity Non-carcinogens 0.7624
Biodegradation Not ready biodegradable 0.9879
Rat acute toxicity 1.9602 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9812
hERG inhibition (predictor II) Non-inhibitor 0.7856
Pharmacoeconomics
Manufacturers
  • Abraxis pharmaceutical products
  • App pharmaceuticals llc
  • Bedford laboratories div ben venue laboratories inc
  • Hospira inc
  • Teva parenteral medicines inc
  • Bayer healthcare pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous
Prices
Unit descriptionCostUnit
Dacarbazine 200 mg vial22.21USDeach
Dacarbazine 100 mg vial11.34USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point205 °CPhysProp
water solubility4220 mg/LNot Available
logP-0.24HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility1.36ALOGPS
logP-0.32ALOGPS
logP-0.43ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)5.89ChemAxon
pKa (Strongest Basic)1.72ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area99.73 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity49.71 m3·mol-1ChemAxon
Polarizability17.78 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00288
ChEBI4305
ChEMBLCHEMBL476
Therapeutic Targets DatabaseDAP000533
PharmGKBPA449197
Drug Product Database2241445
RxListhttp://www.rxlist.com/cgi/generic2/dacarbazine.htm
Drugs.comhttp://www.drugs.com/cdi/dacarbazine.html
WikipediaDacarbazine
ATC CodesL01AX04
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
BendamustineIncreases toxicity through pharmacodynamic synergism. Additive myelosuppression.
ThiabendazoleThe strong CYP1A2 inhibitor, Thiabendazole, may increase the effects and toxicity of Dacarbazine by decreasing Dacarbazine metabolism and clearance. Monitor for changes in the therapeutic and adverse effects of Dacarbazine if Thiabendazole is initiated, discontinued or dose changed.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food InteractionsNot Available

Targets

1. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: cross-linking/alkylation

Components

Name UniProt ID Details

References:

  1. Lonn U, Lohn S: Prevention of dacarbazine damage of human neoplastic cell DNA by aphidicolin. Cancer Res. 1987 Jan 1;47(1):26-30. Pubmed

2. DNA polymerase alpha subunit B

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
DNA polymerase alpha subunit B Q14181 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. Lonn U, Lohn S: Prevention of dacarbazine damage of human neoplastic cell DNA by aphidicolin. Cancer Res. 1987 Jan 1;47(1):26-30. Pubmed

3. 6-phosphogluconate dehydrogenase, decarboxylating

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
6-phosphogluconate dehydrogenase, decarboxylating P52209 Details

References:

  1. Akkemik E, Budak H, Ciftci M: Effects of some drugs on human erythrocyte 6-phosphogluconate dehydrogenase: an in vitro study. J Enzyme Inhib Med Chem. 2010 Mar 17. Pubmed
  2. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed

Enzymes

1. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 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

2. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 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 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 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 October 22, 2013 22:29