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targets (3) enzymes (3)
for drugs
Identification
Name Dacarbazine
Accession Number DB00851 (APRD00331)
Type small molecule
Groups approved
Description

An antineoplastic agent. It has significant activity against melanomas. (from Martindale, The Extra Pharmacopoeia, 31st ed, p564)
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Biocarbazine R
  • Dacarbazino [INN-Spanish]
  • Dacarbazinum [INN-Latin]
  • DTIC
  • Dtic-Dome
  • DTIE
  • ICDMT
  • ICDT
  • Imidazole Carboxamide
Synonyms
Biocarbazine R
Dacarbazino [INN-Spanish]
Dacarbazinum [INN-Latin]
DTIC
Dtic-Dome
DTIE
ICDMT
ICDT
Imidazole Carboxamide
Salts Not Available
Brand names
Name Company
Deticene
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antineoplastic Agents, Alkylating
CAS number 4342-03-4
Weight Average: 182.1832
Monoisotopic: 182.091608972
Chemical Formula C6H10N6O
InChI Key InChIKey=FDKXTQMXEQVLRF-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)
Plain Text
IUPAC Name
5-(dimethyltriaz-1-en-1-yl)-1H-imidazole-4-carboxamide
SMILES
CN(C)N=NC1=C(N=CN1)C(N)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
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.
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.
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
Toxicity LD50=350mg/kg (orally in mice)
Affected organisms
  • Humans and other mammals
Pathways Not Available
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
Form Route Strength
Powder, for solution Intravenous
Prices
Unit description Cost Unit
Dacarbazine 200 mg vial 22.21 USD each
Dacarbazine 100 mg vial 11.34 USD vial
Patents Not Available
Properties
State solid
Melting point 205 oC
Experimental Properties
Property Value Source
water solubility 4220 mg/L PhysProp
logP -1.6 PhysProp
Predicted Properties
Property Value Source
water solubility 1.36e+00 g/l ALOGPS
logP -0.32 ALOGPS
logP -0.43 ChemAxon Molconvert
logS -2.1 ALOGPS
pKa 13.98 ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 99.73 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 49.71 ChemAxon Molconvert
polarizability 17.78 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00288 Link_out
ChEBI 4305 Link_out
ChEMBL 4305 Link_out
Therapeutic Targets Database DAP000533 Link_out
PharmGKB PA449197 Link_out
Drug Product Database 2241445 Link_out
RxList http://www.rxlist.com/cgi/generic2/dacarbazine.htm Link_out
Drugs.com http://www.drugs.com/cdi/dacarbazine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Dacarbazine Link_out
ATC Codes
  • L01AX04
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Thiabendazole The 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.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions Not Available
Targets

1. DNA

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.

Gene Sequence: FASTA

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 subunit alpha B

Pharmacological action: unknown
Actions: other/unknown

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

Organism class: human
UniProt ID: Q14181 Link_out
Gene: POLA2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: inhibitor

6-phospho-D-gluconate + NADP(+) = D-ribulose 5-phosphate + CO(2) + NADPH

Organism class: human
UniProt ID: P52209 Link_out
Gene: PGD Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P04798 Link_out
Gene: CYP1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 or carcinogenic forms

UniProt ID: P05181 Link_out
Gene: CYP2E1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Drug created on June 13, 2005 07:24 / Updated on April 19, 2012 13:15