Details of the Drug

General Information of Drug (ID: DMNPZL4)

Drug Name

Dacarbazine

Synonyms

Biocarbazin; Biocarbazine; DTIC; DTICDome; DTIE; Dacarbazino; Dacarbazinum; Dacatic; Decarbazine; Deticene; Dimethyltriazenoimidazolecarboxamide; ICDMT; ICDT; Biocarbazine R; DTIC Dome; Dimethyl Imidazole Carboxamide; Dimethyl Triazeno Imidazole Carboxamide; Imidazole carboxamide; HE1150000; Carboxamide (TN); Carboxamide, Dimethyl Imidazole; DIC (TN); DTIC (TN); DTIC-Dome; Dacarbazino [INN-Spanish]; Dacarbazinum [INN-Latin]; Imidazole (TN); Imidazole Carboxamide, Dimethyl; NPFAPI-05; DTIC-Dome (TN); Di-me-triazenoimidazolecarboxamide; Di-methyl-triazenoimidazolecarboxamide; Dtic-Dome (TN); DTIC, DTIC-Dome, Dacarbazine; Dacarbazine (JAN/USP/INN); Dacarbazine [USAN:INN:BAN:JAN]; (5E)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide; (5Z)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide; (Dimethyltriazeno)imidazolecarboxamide; 4(5)-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide; 4(5)-(3,3-Dimethyl-1-triazeno)imidazole-5(4)-carboxamide; 4-(3,3-Dimethyl-1-triazeno)imidazole-5-carboxamide; 4-(3,3-Dimethyltriazeno)imidazole-5-carboxamide; 4-(5)-(3,3-Dimethyl-1-triazeno)imidazole-5(4)-carboxamide; 4-(Dimethyltriazeno)imidazole-5-c arboxamide; 4-(Dimethyltriazeno)imidazole-5-carboxamide; 4-(or 5)-(3,3-Dimethyl-1-triazeno)imidazole-5(or 4)-carboxamide; 4-[(1E)-3,3-Dimethyltriaz-1-en-1-yl]-1H-imidazole-5-carboxamide; 4-[3,3-dimethyltriaz-1-en-1-yl]-1H-imidazole-5-carboxamide; 5(or 4)-(dimethyltriazeno)imidazol e-4(or 5)-carboxamide; 5(or 4)-(dimethyltriazeno)imidazole-4(or 5)-carboxamide; 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide; 5-(3,3-Dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide; 5-(3,3-Dimethyl-1-triazenyl)imidazole-4-carboxamide; 5-(3,3-Dimethyltri azeno)imidazole-4-carboxamide; 5-(3,3-Dimethyltriazeno)-imidazole-4-carbamide; 5-(3,3-Dimethyltriazeno)imidazole-4-carboxamide; 5-(3,3-dimethyltriaz-1-en-1-yl)-1H-imidazole-4-carboxamide; 5-(Dimethyltriazeno)-4-imidazolecarboxamide; 5-(Dimethyltriazeno)imidazole-4-carboxamide; 5-(Dimethyltriazeno)imidazole-4-carboximide; 5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide; 5-[3,3-Dimethyl-1-triazenyl]imidazole-4-carboxamide

Indication

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[1]
Astrocytoma	2A00.0Y	Approved	[1]
Brain disease	8C70-8E61	Approved	[1]
Central nervous system disease	8A04-8D87	Approved	[1]
Glioblastoma	2A00	Approved	[1]
Gliosarcoma	N.A.	Approved	[1]
Melanoma	2C30	Approved	[2]
Classic Hodgkin lymphoma	N.A.	Investigative	[1]
Neuroblastoma	2D11.2	Investigative	[1]
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Therapeutic Class

Anticancer Agents

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

182.18

Logarithm of the Partition Coefficient (xlogp)

-0.6

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Absorption: The drug is unstablely, slowly and incompletely absorbed []
BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [3]
Clearance: The drug present in the plasma can be removed from the body at the rate of 2.6 mL/min/kg [4]
Elimination: 39% of drug is excreted from urine in the unchanged form [3]
Half-life: The concentration or amount of drug in body reduced by one-half in 5 hours [4]
Metabolism: The drug is metabolized via the hepatic []
MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 24.7 micromolar/kg/day [5]
Unbound Fraction: The unbound fraction of drug in plasma is 1% [4]
Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 1.2 L/kg [4]
Water Solubility: The ability of drug to dissolve in water is measured as 4.2 mg/mL [3]

Chemical Identifiers

Formula: C6H10N6O
IUPAC Name: 4-[(E)-dimethylaminodiazenyl]-1H-imidazole-5-carboxamide
Canonical SMILES: CN(C)/N=N/C1=C(NC=N1)C(=O)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+
InChIKey: FDKXTQMXEQVLRF-ZHACJKMWSA-N

Cross-matching ID

PubChem CID: 135398738
ChEBI ID: CHEBI:94587
CAS Number: 4342-03-4
DrugBank ID: DB00851
TTD ID: D0Y7ZU
INTEDE ID: DR0404
ACDINA ID: D00979

Combinatorial Drugs (CBD)

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Repurposed Drugs (RPD)

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Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Breaker	[6]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Substrate	[7]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Substrate	[8]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Substrate	[9]

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Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Gene/Protein Processing	[10]
Clusterin (CLU)	OTQGG0JM	CLUS_HUMAN	Drug Response	[11]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Drug Response	[12]
Erythropoietin (EPO)	OTZ90CN4	EPO_HUMAN	Drug Response	[13]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Drug Response	[14]
Interferon regulatory factor 1 (IRF1)	OT43DI6J	IRF1_HUMAN	Gene/Protein Processing	[15]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Gene/Protein Processing	[16]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Gene/Protein Processing	[17]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Drug Response	[18]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Drug Response	[18]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Dacarbazine (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Remdesivir	DMBFZ6L	Moderate	Increased risk of hepatotoxicity by the combination of Dacarbazine and Remdesivir.	1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019]	[19]
Bedaquiline	DM3906J	Moderate	Increased risk of hepatotoxicity by the combination of Dacarbazine and Bedaquiline.	Antimicrobial drug resistance [MG50-MG52]	[20]
Roflumilast	DMPGHY8	Moderate	Additive immunosuppressive effects by the combination of Dacarbazine and Roflumilast.	Asthma [CA23]	[21]
Ofloxacin	DM0VQN3	Minor	Decreased absorption of Dacarbazine due to intestinal mucosa variation caused by Ofloxacin.	Bacterial infection [1A00-1C4Z]	[22]
Sparfloxacin	DMB4HCT	Minor	Decreased absorption of Dacarbazine due to intestinal mucosa variation caused by Sparfloxacin.	Bacterial infection [1A00-1C4Z]	[22]
Gemifloxacin	DMHT34O	Minor	Decreased absorption of Dacarbazine due to intestinal mucosa variation caused by Gemifloxacin.	Bacterial infection [1A00-1C4Z]	[22]
Norfloxacin	DMIZ6W2	Minor	Decreased absorption of Dacarbazine due to intestinal mucosa variation caused by Norfloxacin.	Bacterial infection [1A00-1C4Z]	[22]
ABT-492	DMJFD2I	Minor	Decreased absorption of Dacarbazine due to intestinal mucosa variation caused by ABT-492.	Bacterial infection [1A00-1C4Z]	[22]
Levofloxacin	DMS60RB	Minor	Decreased absorption of Dacarbazine due to intestinal mucosa variation caused by Levofloxacin.	Bacterial infection [1A00-1C4Z]	[22]
Lomefloxacin	DMVRH9C	Minor	Decreased absorption of Dacarbazine due to intestinal mucosa variation caused by Lomefloxacin.	Bacterial infection [1A00-1C4Z]	[22]
Pexidartinib	DMS2J0Z	Major	Increased risk of hepatotoxicity by the combination of Dacarbazine and Pexidartinib.	Bone/articular cartilage neoplasm [2F7B]	[23]
Cannabidiol	DM0659E	Moderate	Increased risk of hepatotoxicity by the combination of Dacarbazine and Cannabidiol.	Epileptic encephalopathy [8A62]	[21]
Brentuximab vedotin	DMWLC57	Moderate	Increased risk of hepatotoxicity by the combination of Dacarbazine and Brentuximab vedotin.	Hodgkin lymphoma [2B30]	[24]
Mipomersen	DMGSRN1	Major	Increased risk of hepatotoxicity by the combination of Dacarbazine and Mipomersen.	Hyper-lipoproteinaemia [5C80]	[25]
BMS-201038	DMQTAGO	Major	Increased risk of hepatotoxicity by the combination of Dacarbazine and BMS-201038.	Hyper-lipoproteinaemia [5C80]	[26]
Denosumab	DMNI0KO	Moderate	Additive myelosuppressive effects by the combination of Dacarbazine and Denosumab.	Low bone mass disorder [FB83]	[27]
Calaspargase pegol	DMQZBXI	Moderate	Increased risk of hepatotoxicity by the combination of Dacarbazine and Calaspargase pegol.	Malignant haematopoietic neoplasm [2B33]	[28]
Idelalisib	DM602WT	Moderate	Increased risk of hepatotoxicity by the combination of Dacarbazine and Idelalisib.	Mature B-cell leukaemia [2A82]	[29]
Thalidomide	DM70BU5	Major	Additive thrombogenic effects by the combination of Dacarbazine and Thalidomide.	Multiple myeloma [2A83]	[30]
Tecfidera	DM2OVDT	Moderate	Additive immunosuppressive effects by the combination of Dacarbazine and Tecfidera.	Multiple sclerosis [8A40]	[31]
Siponimod	DM2R86O	Major	Additive immunosuppressive effects by the combination of Dacarbazine and Siponimod.	Multiple sclerosis [8A40]	[19]
Fingolimod	DM5JVAN	Major	Additive immunosuppressive effects by the combination of Dacarbazine and Fingolimod.	Multiple sclerosis [8A40]	[32]
Ocrelizumab	DMEZ2KH	Moderate	Additive immunosuppressive effects by the combination of Dacarbazine and Ocrelizumab.	Multiple sclerosis [8A40]	[33]
Ozanimod	DMT6AM2	Major	Additive immunosuppressive effects by the combination of Dacarbazine and Ozanimod.	Multiple sclerosis [8A40]	[21]
Omacetaxine mepesuccinate	DMPU2WX	Moderate	Additive immunosuppressive effects by the combination of Dacarbazine and Omacetaxine mepesuccinate.	Myeloproliferative neoplasm [2A20]	[34]
Gatifloxacin	DMSL679	Minor	Decreased absorption of Dacarbazine due to intestinal mucosa variation caused by Gatifloxacin.	Respiratory infection [CA07-CA4Z]	[22]
Canakinumab	DM8HLO5	Moderate	Additive immunosuppressive effects by the combination of Dacarbazine and Canakinumab.	Rheumatoid arthritis [FA20]	[35]
Rilonacept	DMGLUQS	Moderate	Additive immunosuppressive effects by the combination of Dacarbazine and Rilonacept.	Rheumatoid arthritis [FA20]	[35]
Golimumab	DMHZV7X	Major	Additive immunosuppressive effects by the combination of Dacarbazine and Golimumab.	Rheumatoid arthritis [FA20]	[36]
Leflunomide	DMR8ONJ	Major	Additive myelosuppressive effects by the combination of Dacarbazine and Leflunomide.	Rheumatoid arthritis [FA20]	[37]
Anthrax vaccine	DM9GSWY	Moderate	Antagonize the effect of Dacarbazine when combined with Anthrax vaccine.	Sepsis [1G40-1G41]	[38]
Trabectedin	DMG3Y89	Moderate	Increased risk of hepatotoxicity by the combination of Dacarbazine and Trabectedin.	Solid tumour/cancer [2A00-2F9Z]	[21]
Azathioprine	DMMZSXQ	Moderate	Additive immunosuppressive effects by the combination of Dacarbazine and Azathioprine.	Transplant rejection [NE84]	[19]
Ganciclovir	DM1MBYQ	Moderate	Additive myelosuppressive effects by the combination of Dacarbazine and Ganciclovir.	Virus infection [1A24-1D9Z]	[19]
Valganciclovir	DMS2IUH	Moderate	Additive myelosuppressive effects by the combination of Dacarbazine and Valganciclovir.	Virus infection [1A24-1D9Z]	[19]
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Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Kyselina citronova	E00014	311	Acidulant; Antioxidant; Buffering agent; Complexing agent; Flavoring agent
Mannitol	E00103	6251	Diluent; Flavoring agent; Lyophilization aid; Plasticizing agent; Tonicity agent
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Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Dacarbazine 200mg/vial injectable	200mg/vial	Injectable	Injection

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References

1	Dacarbazine FDA Label
2	FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075259.
3	BDDCS applied to over 900 drugs
4	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
5	Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
6	Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mono... Melanoma Res. 2011 Dec;21(6):502-8.
7	Role of cytochrome P450 isoenzymes in metabolism of O(6)-benzylguanine: implications for dacarbazine activation. Clin Cancer Res. 2001 Dec;7(12):4239-44.
8	Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1, CYP1A2, and CYP2E1. Clin Cancer Res. 1999 Aug;5(8):2192-7.
9	Study on mesenchymal stem cells mediated enzyme-prodrug gene CYP1A2 targeting anti-tumor effect. Zhonghua Xue Ye Xue Za Zhi. 2009 Oct;30(10):667-71.
10	Serum bcl-2 and survivin levels in melanoma. Melanoma Res. 2004 Dec;14(6):543-6. doi: 10.1097/00008390-200412000-00017.
11	Clusterin regulates drug-resistance in melanoma cells. J Invest Dermatol. 2005 Jun;124(6):1300-7. doi: 10.1111/j.0022-202X.2005.23720.x.
12	Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906. doi: 10.1158/1541-7786.MCR-08-0519. Epub 2009 May 26.
13	Functional erythropoietin autocrine loop in melanoma. Am J Pathol. 2005 Mar;166(3):823-30. doi: 10.1016/S0002-9440(10)62303-6.
14	Mcl-1 antisense therapy chemosensitizes human melanoma in a SCID mouse xenotransplantation model. J Invest Dermatol. 2003 Jun;120(6):1081-6. doi: 10.1046/j.1523-1747.2003.12252.x.
15	CD69 on CD56+ NK cells and response to chemoimmunotherapy in metastatic melanoma. Eur J Clin Invest. 2007 Nov;37(11):887-96. doi: 10.1111/j.1365-2362.2007.01873.x.
16	Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther. 2003 Aug;2(8):753-63.
17	Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer. Int J Cancer. 2003 Feb 20;103(5):686-92. doi: 10.1002/ijc.10849.
18	Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol. 2004 Jun 1;22(11):2092-100. doi: 10.1200/JCO.2004.11.070. Epub 2004 May 3.
19	Cerner Multum, Inc. "Australian Product Information.".
20	Product Information. Sirturo (bedaquiline). Janssen Pharmaceuticals, Titusville, NJ.
21	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
22	Johnson EJ, MacGowan AP, Potter MN, et al "Reduced absorption of oral ciprofloxacin after chemotherapy for haematological malignancy." J Antimicrob Chemother 25 (1990): 837-42. [PMID: 2373666]
23	Product Information. Turalio (pexidartinib). Daiichi Sankyo, Inc., Parsippany, NJ.
24	Product Information. Adcetris (brentuximab vedotin). Seattle Genetics Inc, Bothell, WA.
25	Product Information. Kynamro (mipomersen). Genzyme Corporation, Cambridge, MA.
26	Product Information. Juxtapid (lomitapide). Aegerion Pharmaceuticals Inc, Cambridge, MA.
27	Product Information. Prolia (denosumab). Amgen USA, Thousand Oaks, CA.
28	Al-Nawakil C, Willems L, Mauprivez C, et.al "Successful treatment of l-asparaginase-induced severe acute hepatotoxicity using mitochondrial cofactors." Leuk Lymphoma 55 (2014): 1670-4. [PMID: 24090500]
29	Product Information. Zydelig (idelalisib). Gilead Sciences, Foster City, CA.
30	Bennett CL, Nebeker JR, Samore MH, et al "The Research on Adverse Drug Events and Reports (RADAR) project." JAMA 293 (2005): 2131-40. [PMID: 15870417]
31	Product Information. Vumerity (diroximel fumarate). Alkermes, Inc, Cambridge, MA.
32	Product Information. Gilenya (fingolimod). Novartis Pharmaceuticals, East Hanover, NJ.
33	Product Information. Ocrevus (ocrelizumab). Genentech, South San Francisco, CA.
34	Product Information. Synribo (omacetaxine). Teva Pharmaceuticals USA, North Wales, PA.
35	Product Information. Arcalyst (rilonacept). Regeneron Pharmaceuticals Inc, Tarrytown, NY.
36	Product Information. Cimzia (certolizumab). UCB Pharma Inc, Smyrna, GA.
37	Product Information. Arava (leflunomide). Hoechst Marion-Roussel Inc, Kansas City, MO.
38	CDC. Centers for Disease Control and Prevention/ "Recommendations of the advisory committtee on immunization practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence." MMWR Morb Mortal Wkly Rep 42(RR-04) (1993): 1-18. [PMID: 20300058]