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Identification
NameCarmustine
Accession NumberDB00262  (APRD00006)
TypeSmall Molecule
GroupsApproved
Description

A cell-cycle phase nonspecific alkylating antineoplastic agent. It is used in the treatment of brain tumors and various other malignant neoplasms. (From Martindale, The Extra Pharmacopoeia, 30th ed, p462) This substance may reasonably be anticipated to be a carcinogen according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (From Merck Index, 11th ed)

Structure
Thumb
Synonyms
BCNU
Bicnu (tn)
bis-chloroethylnitrosourea
Bischloroethyl nitrosourea
Carmustina
Carmustine
Carmustinum
Gliadel
N,N'-Bis(2-chloroethyl)-N-nitrosourea
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BicnukitHeritage Pharmaceuticals Inc.2013-04-04Not applicableUs
Bicnupowder for solution100 mgintravenousHeritage Pharmaceuticals Inc1975-12-31Not applicableCanada
Gliadelwafer7.7 mg/1intracavitaryEisai Inc.1996-09-24Not applicableUs
Gliadelwafer7.7 mg/1intracavitaryArbor Pharmaceuticals2012-12-13Not applicableUs
Gliadel Waferwafer7.7 mgintralesionalEisai Limited2002-07-022015-03-02Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
BecenunNot Available
CarmubrisNot Available
CarustineCuracell Biotech
NitrumonNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIU68WG3173Y
CAS number154-93-8
WeightAverage: 214.05
Monoisotopic: 213.007181961
Chemical FormulaC5H9Cl2N3O2
InChI KeyInChIKey=DLGOEMSEDOSKAD-UHFFFAOYSA-N
InChI
InChI=1S/C5H9Cl2N3O2/c6-1-3-8-5(11)10(9-12)4-2-7/h1-4H2,(H,8,11)
IUPAC Name
1,3-bis(2-chloroethyl)-3-nitrosourea
SMILES
ClCCNC(=O)N(CCCl)N=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as nitrosoureas. These are compounds containing a nitro group and an urea group N-N linked together, with the general structure R1N(R2)C(=O)N(R3)N=O.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassOrganic carbonic acids and derivatives
Sub ClassUreas
Direct ParentNitrosoureas
Alternative Parents
Substituents
  • Nitrosourea
  • Nitrosamide
  • Semicarbazide
  • Organic nitrosamine
  • N-nitroso compound
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Alkyl halide
  • Alkyl chloride
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of brain tumors, multiple myeloma, Hodgkin's disease and Non-Hodgkin's lymphomas.
PharmacodynamicsCarmustine is one of the nitrosoureas indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in treatment of brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Although it is generally agreed that carmustine alkylates DNA and RNA, it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.
Mechanism of actionCarmustine causes cross-links in DNA and RNA, leading to the inhibition of DNA synthesis, RNA production and RNA translation (protein synthesis). Carmustine also binds to and modifies (carbamoylates) glutathione reductase. This leads to cell death.
Related Articles
Absorption5 to 28% bioavailability
Volume of distributionNot Available
Protein binding80%
Metabolism

Hepatic and rapid with active metabolites. Metabolites may persist in the plasma for several days.

Route of eliminationApproximately 60% to 70% of a total dose is excreted in the urine in 96 hours and about 10% as respiratory CO2.
Half life15-30 minutes
ClearanceNot Available
ToxicityThe oral LD50s in rat and mouse are 20 mg/kg and 45 mg/kg, respectively. Side effects include leukopenia, thrombocytopenia, nausea. Toxic effects include pulmonary fibrosis (20-0%) and bone marrow toxicity.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9533
Caco-2 permeable-0.5621
P-glycoprotein substrateNon-substrate0.7552
P-glycoprotein inhibitor INon-inhibitor0.797
P-glycoprotein inhibitor IINon-inhibitor0.8778
Renal organic cation transporterNon-inhibitor0.8177
CYP450 2C9 substrateNon-substrate0.7656
CYP450 2D6 substrateNon-substrate0.8491
CYP450 3A4 substrateNon-substrate0.672
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.9031
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9131
Ames testAMES toxic0.9577
CarcinogenicityCarcinogens 0.688
BiodegradationNot ready biodegradable0.5596
Rat acute toxicity3.9975 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.7278
hERG inhibition (predictor II)Non-inhibitor0.919
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Eisai inc
  • Bristol laboratories inc div bristol myers co
Packagers
Dosage forms
FormRouteStrength
Kit
Powder for solutionintravenous100 mg
Waferintracavitary7.7 mg/1
Waferintralesional7.7 mg
Prices
Unit descriptionCostUnit
Gliadel Wafer 8 7.7 mg Wafers Box22611.26USD box
Gliadel wafer3667.95USD each
Bicnu 100 mg vial205.69USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point31 °CPhysProp
water solubility4000 mg/L (at 25 °C)MERCK (1989)
logP1.53HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility1.53 mg/mLALOGPS
logP1.24ALOGPS
logP1.02ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)11.96ChemAxon
pKa (Strongest Basic)-5.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area61.77 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity46.98 m3·mol-1ChemAxon
Polarizability18.8 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesL01AD01
AHFS Codes
  • 10:00.00
PDB Entries
FDA labelDownload (4.55 MB)
MSDSDownload (195 KB)
Interactions
Drug Interactions
Drug
CimetidineCimetidine may increase the myelosuppressive activities of Carmustine.
ClozapineThe risk or severity of adverse effects can be increased when Carmustine is combined with Clozapine.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Carmustine.
L-PhenylalanineThe risk or severity of adverse effects can be increased when L-Phenylalanine is combined with Carmustine.
LeflunomideThe risk or severity of adverse effects can be increased when Carmustine is combined with Leflunomide.
MelphalanThe risk or severity of adverse effects can be increased when Melphalan is combined with Carmustine.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Carmustine.
NatalizumabThe risk or severity of adverse effects can be increased when Carmustine is combined with Natalizumab.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Carmustine.
RoflumilastRoflumilast may increase the immunosuppressive activities of Carmustine.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Carmustine.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Carmustine.
TofacitinibCarmustine may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Carmustine.
Food Interactions
  • Echinacea

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Nadp binding
Specific Function:
Maintains high levels of reduced glutathione in the cytosol.
Gene Name:
GSR
Uniprot ID:
P00390
Molecular Weight:
56256.565 Da
References
  1. Akella SS, Harris C: Pyridine nucleotide flux and glutathione oxidation in the cultured rat conceptus. Reprod Toxicol. 1999 May-Jun;13(3):203-13. [PubMed:10378469 ]
  2. Kirsch JD, Yi AK, Spitz DR, Krieg AM: Accumulation of glutathione disulfide mediates NF-kappaB activation during immune stimulation with CpG DNA. Antisense Nucleic Acid Drug Dev. 2002 Oct;12(5):327-40. [PubMed:12477282 ]
  3. Vallyathan V, Mega JF, Shi X, Dalal NS: Enhanced generation of free radicals from phagocytes induced by mineral dusts. Am J Respir Cell Mol Biol. 1992 Apr;6(4):404-13. [PubMed:1312851 ]
  4. Brodie AE, Reed DJ: Glutathione disulfide reduction in tumor mitochondria after t-butyl hydroperoxide treatment. Chem Biol Interact. 1992 Sep 28;84(2):125-32. [PubMed:1394620 ]
  5. Jopperi-Davis KS, Park MS, Rogers LK, Backes CH Jr, Lim IK, Smith CV: Compartmental inhibition of hepatic glutathione reductase activities by 1,3-bis(2-chloroethyl)-N-nitrosourea (BCNU) in Sprague-Dawley and Fischer-344 rats. Toxicol Lett. 2004 Mar 7;147(3):219-28. [PubMed:15104113 ]
  6. Doroshenko N, Doroshenko P: The glutathione reductase inhibitor carmustine induces an influx of Ca2+ in PC12 cells. Eur J Pharmacol. 2004 Aug 16;497(1):17-24. [PubMed:15321730 ]
  7. Powell SR, Puglia CD: Effect of inhibition of glutathione reductase by carmustine on central nervous system oxygen toxicity. J Pharmacol Exp Ther. 1987 Jan;240(1):111-7. [PubMed:3806383 ]
  8. Puglia CD, Powell SR: Inhibition of cellular antioxidants: a possible mechanism of toxic cell injury. Environ Health Perspect. 1984 Aug;57:307-11. [PubMed:6094175 ]
2. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
other/unknown
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. 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 ]
  2. Johannessen TC, Bjerkvig R, Tysnes BB: DNA repair and cancer stem-like cells--potential partners in glioma drug resistance? Cancer Treat Rev. 2008 Oct;34(6):558-67. doi: 10.1016/j.ctrv.2008.03.125. Epub 2008 May 22. [PubMed:18501520 ]
  3. Lin SH, Kleinberg LR: Carmustine wafers: localized delivery of chemotherapeutic agents in CNS malignancies. Expert Rev Anticancer Ther. 2008 Mar;8(3):343-59. doi: 10.1586/14737140.8.3.343. [PubMed:18366283 ]
  4. Drablos F, Feyzi E, Aas PA, Vaagbo CB, Kavli B, Bratlie MS, Pena-Diaz J, Otterlei M, Slupphaug G, Krokan HE: Alkylation damage in DNA and RNA--repair mechanisms and medical significance. DNA Repair (Amst). 2004 Nov 2;3(11):1389-407. [PubMed:15380096 ]
  5. Zhang Q, Ohannesian DW, Kreklau EL, Erickson LC: Modulation of 1,3-bis-(2-chloroethyl)-1-nitrosourea resistance in human tumor cells using hammerhead ribozymes designed to degrade O6-methylguanine DNA methyltransferase mRNA. J Pharmacol Exp Ther. 2001 Jul;298(1):141-7. [PubMed:11408535 ]
  6. He YH, Xu Y, Kobune M, Wu M, Kelley MR, Martin WJ 2nd: Escherichia coli FPG and human OGG1 reduce DNA damage and cytotoxicity by BCNU in human lung cells. Am J Physiol Lung Cell Mol Physiol. 2002 Jan;282(1):L50-5. [PubMed:11741815 ]
3. RNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
other/unknown
References
  1. Lin SH, Kleinberg LR: Carmustine wafers: localized delivery of chemotherapeutic agents in CNS malignancies. Expert Rev Anticancer Ther. 2008 Mar;8(3):343-59. doi: 10.1586/14737140.8.3.343. [PubMed:18366283 ]

Enzymes

Kind
Protein
Organism
Human
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 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 N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23