Identification

Name
Dacarbazine
Accession Number
DB00851
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.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 182.187
Monoisotopic: 182.091608966
Chemical Formula
C6H10N6O
Synonyms
  • 4-(3,3-dimethyl-1-triazeno)imidazole-5-carboxamide
  • 4-(5)-(3,3-dimethyl-1-triazeno)imidazole-5(4)-carboxamide
  • 4-(dimethyltriazeno)imidazole-5-carboxamide
  • 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide
  • 5-(3,3-dimethyltriazeno)imidazole-4-carboxamide
  • 5-(dimethyltriazeno)imidazole-4-carboxamide
  • Biocarbazine
  • Dacarbazin
  • Dacarbazina
  • Dacarbazine
  • Dacarbazinum
  • DIC
  • DTIC
  • ICDMT
External IDs
  • HSDB 3219
  • NCI C04717
  • NCI-C04717
  • NSC 45 388
  • NSC 45388
  • NSC-45388

Pharmacology

Indication

For 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.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Dacarbazine 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 action

The 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.

TargetActionsOrganism
ADNA
cross-linking/alkylation
Humans
UDNA polymerase alpha subunit B
other/unknown
Humans
U6-phosphogluconate dehydrogenase, decarboxylating
inhibitor
Humans
Absorption

Erratic, slow and incomplete.

Volume of distribution
Not Available
Protein binding

Less than 5%

Metabolism

Hepatic

Route of elimination

Dacarbazine 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-life

5 hours

Clearance
Not Available
Adverse Effects
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Toxicity

LD50=350mg/kg (orally in mice)

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirDacarbazine may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbametapirThe serum concentration of Dacarbazine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Dacarbazine can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Dacarbazine.
AbirateroneThe serum concentration of Dacarbazine can be increased when it is combined with Abiraterone.
AcarboseAcarbose may decrease the excretion rate of Dacarbazine which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Dacarbazine which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Dacarbazine which could result in a higher serum level.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Dacarbazine.
AcetaminophenThe metabolism of Dacarbazine can be decreased when combined with Acetaminophen.
Additional Data Available
  • Extended Description
    Extended Description
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    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity
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    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level
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  • Action
    Action
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    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take on an empty stomach. Fasting for four to six hours before treatment may be beneficial to reduce nausea and vomiting associated with Dacarbazine therapy.

Products

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International/Other Brands
Dacatic (Orion Corporation) / Déticène (Sanofi-Aventis) / Deticene (Sanofi-Aventis) / Detimedac (medac GmbH) / DTIC (Bayer AG) / DTIC-Dome (Bayer Schering)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Dacarbazine for Injection BPPowder, for solutionIntravenousPfizer Canada Ulc2000-04-04Not applicableCanada flag
Dtic Dome Inj 200mg/vialLiquidIntravenousMiles Canada Inc. Pharmaceutical Division1976-12-311998-09-25Canada flag
Dtic-dome -pws IV 200mg/vialPowder, for solutionIntravenousBayer1996-10-102005-05-31Canada flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DacarbazineInjection, powder, for solution200 mg/20mLIntravenousTeva Parenteral Medicines, Inc.1998-08-27Not applicableUS flag
DacarbazineInjection, powder, for solution10 mg/1mLIntravenousFresenius Kabi USA, LLC2001-09-07Not applicableUS flag
DacarbazineInjection, powder, lyophilized, for solution10 mg/1mLIntravenousBedford Pharmaceuticals2001-08-082013-05-31US flag
DacarbazineInjection, powder, for solution10 mg/1mLIntravenousFresenius Kabi USA, LLC2001-09-07Not applicableUS flag
DacarbazineInjection, powder, for solution10 mg/1mLIntravenousHospira, Inc.2003-07-01Not applicableUS flag
DacarbazineInjection, powder, lyophilized, for solution10 mg/1mLIntravenousHikma Pharmaceuticals USA Inc.2001-08-08Not applicableUS flag
DacarbazineInjection, powder, lyophilized, for solution200 mg/20mLIntravenousBedford Pharmaceuticals2008-03-032012-12-31US flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

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Categories

ATC Codes
L01AX04 — Dacarbazine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 2-heteroaryl carboxamides. These are compounds containing a heteroaromatic ring that carries a carboxamide group.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Carboxylic acid derivatives
Direct Parent
2-heteroaryl carboxamides
Alternative Parents
Carbonylimidazoles / Vinylogous amides / Heteroaromatic compounds / Primary carboxylic acid amides / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Organooxygen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
2-heteroaryl carboxamide / Aromatic heteromonocyclic compound / Azacycle / Azole / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Imidazole-4-carbonyl group / Organic 1,3-dipolar compound / Organic nitrogen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
7GR28W0FJI
CAS number
4342-03-4
InChI Key
FDKXTQMXEQVLRF-ZHACJKMWSA-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)/b11-10+
IUPAC Name
5-[(1E)-3,3-dimethyltriaz-1-en-1-yl]-1H-imidazole-4-carboxamide
SMILES
CN(C)\N=N\C1=C(N=CN1)C(N)=O

References

General References
Not Available
KEGG Drug
D00288
KEGG Compound
C06936
PubChem Compound
5351166
PubChem Substance
46507029
ChemSpider
10481959
BindingDB
50238687
RxNav
3098
ChEBI
4305
ChEMBL
CHEMBL476
ZINC
ZINC000100019007
Therapeutic Targets Database
DAP000533
PharmGKB
PA449197
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dacarbazine
AHFS Codes
  • 10:00.00 — Antineoplastic Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
4RecruitingTreatmentPediatric Hodgkin's Disease1
4Unknown StatusTreatmentMetastatic Melanoma1
3Active Not RecruitingTreatmentLocalized High-risk Soft Tissue Sarcomas of the Extremities and Trunk Wall in Adults1
3Active Not RecruitingTreatmentLymphoma, Hodgkins2
3Active Not RecruitingTreatmentMalignant Lymphomas1
3Active Not RecruitingTreatmentMelanoma1
3Active Not RecruitingTreatmentUnresectable or Metastatic Melanoma1
3CompletedTreatmentAdvanced Liposarcoma or Leiomyosarcoma1
3CompletedTreatmentAdvanced or Metastatic Liposarcoma or Leiomyosarcoma1

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
  • APP Pharmaceuticals
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • Hospira Inc.
  • Sicor Pharmaceuticals
  • Teva Pharmaceutical Industries Ltd.
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous200 mg
Injection, powder, lyophilized, for solutionIntravenous25 mg
Injection, powder, for solutionParenteral1000 mg
Injection, powder, for solutionParenteral200 mg
Injection, powder, for solutionParenteral500 mg
Injection, powder, lyophilized, for solutionIntravenous100 mg
Injection, powder, lyophilized, for solutionIntravenous200 mg
Injection, powder, for solution200 mg
Injection, powder, for solutionIntravenous10 mg/1mL
Injection, powder, for solutionIntravenous200 mg/20mL
Injection, powder, lyophilized, for solutionIntravenous10 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous200 mg/20mL
Injection, powder, for solution100 mg
Injection, powder, for solutionIntravenous1 g
Injection, powder, for solutionIntravenous500 mg
Injection, powder, for solutionParenteral100 mg
PowderIntravenous100 mg
PowderIntravenous200 mg
Injection, powder, for solution
LiquidIntravenous
Powder, for solutionIntravenous
Prices
Unit descriptionCostUnit
Dacarbazine 200 mg vial22.21USD each
Dacarbazine 100 mg vial11.34USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)205 °CPhysProp
water solubility4220 mg/LNot Available
logP-0.24HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility1.36 mg/mLALOGPS
logP-0.32ALOGPS
logP-0.43ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)6.64ChemAxon
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
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9923
Blood Brain Barrier+0.9382
Caco-2 permeable+0.5278
P-glycoprotein substrateNon-substrate0.6608
P-glycoprotein inhibitor INon-inhibitor0.8478
P-glycoprotein inhibitor IINon-inhibitor0.9363
Renal organic cation transporterNon-inhibitor0.9125
CYP450 2C9 substrateNon-substrate0.7898
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.579
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9496
CYP450 2D6 inhibitorNon-inhibitor0.9413
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.99
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8208
Ames testAMES toxic0.9107
CarcinogenicityNon-carcinogens0.7624
BiodegradationNot ready biodegradable0.9879
Rat acute toxicity1.9602 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9812
hERG inhibition (predictor II)Non-inhibitor0.7856
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Cross-linking/alkylation
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
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:3098406]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Other/unknown
General Function
Protein heterodimerization activity
Specific Function
May play an essential role at the early stage of chromosomal DNA replication by coupling the polymerase alpha/primase complex to the cellular replication machinery.
Gene Name
POLA2
Uniprot ID
Q14181
Uniprot Name
DNA polymerase alpha subunit B
Molecular Weight
65947.165 Da
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:17139284]
  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:17016423]
  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:3098406]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Phosphogluconate dehydrogenase (decarboxylating) activity
Specific Function
Catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate and CO(2), with concomitant reduction of NADP to NADPH.
Gene Name
PGD
Uniprot ID
P52209
Uniprot Name
6-phosphogluconate dehydrogenase, decarboxylating
Molecular Weight
53139.56 Da
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 Aug;25(4):476-9. doi: 10.3109/14756360903257900. [PubMed:20235752]
  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:10592235]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d 24-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Reid JM, Kuffel MJ, Miller JK, Rios R, Ames MM: Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1, CYP1A2, and CYP2E1. Clin Cancer Res. 1999 Aug;5(8):2192-7. [PubMed:10473105]
  2. Lewis BC, Mackenzie PI, Miners JO: Application of homology modeling to generate CYP1A1 mutants with enhanced activation of the cancer chemotherapeutic prodrug dacarbazine. Mol Pharmacol. 2011 Nov;80(5):879-88. doi: 10.1124/mol.111.072124. Epub 2011 Aug 4. [PubMed:21816953]
  3. BC Cancer website [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Reid JM, Kuffel MJ, Miller JK, Rios R, Ames MM: Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1, CYP1A2, and CYP2E1. Clin Cancer Res. 1999 Aug;5(8):2192-7. [PubMed:10473105]
  2. Kantrowitz-Gordon I, Hays K, Kayode O, Kumar AR, Kaplan HG, Reid JM, Safgren SL, Ames MM, Easterling TR, Hebert MF: Pharmacokinetics of dacarbazine (DTIC) in pregnancy. Cancer Chemother Pharmacol. 2018 Mar;81(3):455-460. doi: 10.1007/s00280-017-3511-6. Epub 2018 Jan 5. [PubMed:29305638]
  3. Dacarbazine monograph [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Reid JM, Kuffel MJ, Miller JK, Rios R, Ames MM: Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1, CYP1A2, and CYP2E1. Clin Cancer Res. 1999 Aug;5(8):2192-7. [PubMed:10473105]
  2. Long L, Dolan ME: Role of cytochrome P450 isoenzymes in metabolism of O(6)-benzylguanine: implications for dacarbazine activation. Clin Cancer Res. 2001 Dec;7(12):4239-44. [PubMed:11751525]

Drug created on June 13, 2005 07:24 / Updated on November 25, 2020 08:52

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