DACARBAZINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C6H10N6O
Molecular Weight	182.1832
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

SMILES

CN(C)\N=N\C1=C(N=CN1)C(N)=O

InChI

InChIKey=FDKXTQMXEQVLRF-ZHACJKMWSA-N

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+

HIDE SMILES / InChI

Molecular Formula	C6H10N6O
Molecular Weight	182.1832
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

Description

Dacarbazine (DTIC), also known as imidazole carboxamide, is an antineoplastic agent, which is used in the treatment of metastatic malignant melanoma. In addition, this drug also is indicated for Hodgkin’s disease as a second-line therapy when used in combination with other effective agents. Dacarbazine works by methylating guanine at the O-6 and N-7 positions. Guanine is one of the four nucleotides that makes up DNA. The alkylated DNA strands stick together such that cell division becomes impossible. This affects cancer cells more than healthy cells because cancer cells divide faster. Dacarbazine is bioactivated in liver by demethylation to "MTIC" and then to diazomethane, which is an alkylating agent. Symptoms of anorexia, nausea, and vomiting are the most frequently noted of all toxic reactions. Over 90% of patients are affected with the initial few doses.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 278	Inhibitor 8,297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Malignant melanoma 22	Primary		Approved 8,429	DTIC-DOME
Hodgkin's lymphoma 34	Primary		Approved 8,429	DTIC-DOME

C_max

Value	Dose	Co-administered	Analyte	Population
6.2 μg/mL	750 mg/m² single, intravenous		DACARBAZINE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
14.8 μM × min	750 mg/m² single, intravenous		DACARBAZINE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
41.4 min	750 mg/m² single, intravenous		DACARBAZINE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
95%			DACARBAZINE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
1000 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose	unhealthy, 34–79 n = 3	Disc. AE: Cerebral ischemia...
800 mg/m2 1 times / 3 weeks multiple, intravenous MTD	unhealthy, 34–79 n = 16	DLT: Thrombocytopenia... Disc. AE: Thrombocytopenia...
1000 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose	unhealthy, 40–65 n = 45	Other AEs: Neutropenia, Fatigue...
250 mg/m2 1 times / day multiple, intravenous Recommended	unhealthy	Disc. AE: Leukopenia, Thrombocytopenia...
850 mg/m2 1 times / 3 weeks multiple, intravenous Recommended	unhealthy	Disc. AE: Anemia, Leukopenia...

Showing 1 to 5 of 5 entries

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AEs

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AE	Significance	Dose	Population
Cerebral ischemia	grade 4, 33% Disc. AE	1000 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose	unhealthy, 34–79 n = 3
Thrombocytopenia	grade 1, 6.25% Disc. AE	800 mg/m2 1 times / 3 weeks multiple, intravenous MTD	unhealthy, 34–79 n = 16
Thrombocytopenia	grade 2, 6.25% DLT	800 mg/m2 1 times / 3 weeks multiple, intravenous MTD	unhealthy, 34–79 n = 16
Fatigue	grade 4, 2.2%	1000 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose	unhealthy, 40–65 n = 45
Neutropenia	grade 4, 2.2%	1000 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose	unhealthy, 40–65 n = 45

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737	substrate 1,037

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1,478	CYP1A2 1,054 CYP1A1 349 CYP2E1 667

Drug as perpetrator

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Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C19 1,553	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity
CYP2C9 1,037	substrate 3,367	no
CYP3A4 1,737	substrate 3,367	no
CYP1A1 349	substrate 3,367	yes
CYP1A2 1,054	substrate 3,367	yes
CYP2E1 667	substrate 3,367	yes

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:4305	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4305
MolPort	MolPort-044-723-991	https://www.molport.com/shop/molecule-link/MolPort-044-723-991
ZINC	ZINC000254748682	http://zinc15.docking.org/substances/ZINC000254748682
eMolecules	37036088	https://www.emolecules.com/cgi-bin/more?vid=37036088

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PubMed

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Title	Date	PubMed
Toxicity, mutation frequency and mutation spectrum induced by dacarbazine in CHO cells expressing different levels of O(6)-methylguanine-DNA methyltransferase.	2000 Feb 14	10751609
Inhibition of melanoma growth and metastasis by combination with (-)-epigallocatechin-3-gallate and dacarbazine in mice.	2001	11746506
Role of cytochrome P450 isoenzymes in metabolism of O(6)-benzylguanine: implications for dacarbazine activation.	2001 Dec	11751525
The role of glucocorticoids in the treatment of fulminant hepatitis induced by dacarbazine.	2002 Feb	11901312
Chemoimmunotherapy for melanoma with dacarbazine and 2,4-dinitrochlorobenzene elicits a specific T cell-dependent immune response.	2002 Oct	12202904

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Patents

Sample Use Guides

In Vivo Use Guide

Malignant Melanoma: the recommended dosage is 2 to 4.5 mg/kg/day for 10 days. Treatment may be repeated at 4 week intervals Hodgkin's Disease: The recommended dosage of Dacarbazine for Injection, USP in the treatment of Hodgkin’s disease is 150 mg/square meter body surface/day for 5 days, in combination with other effective drugs. Treatment may be repeated every 4 weeks.5 An alternative recommended dosage is 375 mg/square meter body surface on day 1, in combination with other effective drugs, to be repeated every 15 days

Route of Administration: Intravenous

In Vitro Use Guide

The effect of alkyating agent dacarbazine (DTIC) and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo.