Carmustine

Identification

Summary

Carmustine is an alkylating agent used in the treatment of various malignancies, including brain tumours and multiple myeloma, among others.

Brand Names
Bicnu, Gliadel
Generic Name
Carmustine
DrugBank Accession Number
DB00262
Background

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)

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 214.05
Monoisotopic: 213.007181961
Chemical Formula
C5H9Cl2N3O2
Synonyms
  • BCNU
  • bis-chloroethylnitrosourea
  • Bischloroethyl nitrosourea
  • Carmustina
  • Carmustine
  • Carmustinum
  • N,N'-Bis(2-chloroethyl)-N-nitrosourea
External IDs
  • DTI-015
  • FDA-0345
  • NSC-409962
  • SK 27702
  • SK-27702
  • SRI 1720
  • SRI-1720

Pharmacology

Indication

For the treatment of brain tumors, multiple myeloma, Hodgkin's disease and Non-Hodgkin's lymphomas.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Carmustine 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 action

Carmustine 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.

TargetActionsOrganism
ADNA
other/unknown
Humans
AGlutathione reductase, mitochondrial
inhibitor
Humans
ARNA
other/unknown
Humans
Absorption

5 to 28% bioavailability

Volume of distribution

Not Available

Protein binding

80%

Metabolism

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

Route of elimination

Approximately 60% to 70% of a total dose is excreted in the urine in 96 hours and about 10% as respiratory CO2.

Half-life

15-30 minutes

Clearance

Not Available

Adverse Effects
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Toxicity

The 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.

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
AbacavirCarmustine may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbametapirThe serum concentration of Carmustine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Carmustine can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Carmustine.
AbirateroneThe serum concentration of Carmustine can be increased when it is combined with Abiraterone.
AceclofenacAceclofenac may decrease the excretion rate of Carmustine which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Carmustine which could result in a higher serum level.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Carmustine.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Carmustine.
AcetazolamideAcetazolamide may increase the excretion rate of Carmustine which could result in a lower serum level and potentially a reduction in efficacy.
Interactions
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Food Interactions
  • Avoid echinacea.

Products

Products
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International/Other Brands
Becenun / Carmubris / Carustine (Curacell Biotech) / Nitrumon
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BiCNUPowder, for solution100 mg / vialIntravenousMarcan Pharmaceuticals Inc1975-12-31Not applicableCanada flag
BiCNUKit100 mg/30mLIntravenousHeritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc.2013-04-04Not applicableUS flag
BicnuKit100 mg/30mLIntravenousE.R. Squibb & Sons, L.L.C.2009-06-012015-09-30US flag
Carmustine ObviusInjection, powder, for solution100 mgIntravenousObvius Investment B.V.2020-12-16Not applicableEU flag
GliadelWafer7.7 mg/1IntracavitaryEisai Limited1996-09-242010-05-14US flag
GliadelWafer7.7 mg/1IntracavitaryArbor Pharmaceuticals2012-12-13Not applicableUS flag
Gliadel WaferWafer7.7 mgIntralesionalEisai Limited2002-07-022015-03-02Canada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Carmustine100 mg/30mLIntravenousHeritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc.2021-03-01Not applicableUS flag
Carmustine100 mg/30mLIntravenousHeritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc.2019-10-01Not applicableUS flag
Carmustine100 mg/30mLIntravenousZydus Pharmaceuticals USA Inc.2020-12-24Not applicableUS flag
Carmustine100 mg/30mLIntravenousSandoz Inc.2021-05-26Not applicableUS flag
Carmustine100 mg/30mLIntravenousSTI Pharma LLC2019-05-16Not applicableUS flag
Carmustine100 mg/30mLIntravenousAmneal Pharmaceuticals LLC2018-10-22Not applicableUS flag
Carmustine100 mg/30mLIntravenousNavinta Llc2020-12-29Not applicableUS flag

Categories

ATC Codes
L01AD01 — Carmustine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This 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.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Organic carbonic acids and derivatives
Sub Class
Ureas
Direct Parent
Nitrosoureas
Alternative Parents
Semicarbazides / Nitrosamides / Organopnictogen compounds / Organochlorides / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds / Alkyl chlorides
Substituents
Aliphatic acyclic compound / Alkyl chloride / Alkyl halide / Carbonyl group / Hydrocarbon derivative / Nitrosamide / Nitrosourea / Organic n-nitroso compound / Organic nitrogen compound / Organic nitroso compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
organochlorine compound, N-nitrosoureas (CHEBI:3423)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
U68WG3173Y
CAS number
154-93-8
InChI Key
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

References

General References
  1. FDA Approved Drug Products: BiCNU (carmustine) for intravenous injection [Link]
Human Metabolome Database
HMDB0014407
KEGG Drug
D00254
KEGG Compound
C06873
PubChem Compound
2578
PubChem Substance
46506980
ChemSpider
2480
BindingDB
50015950
RxNav
2105
ChEBI
3423
ChEMBL
CHEMBL513
ZINC
ZINC000003830387
Therapeutic Targets Database
DAP000041
PharmGKB
PA448810
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Carmustine
FDA label
Download (4.55 MB)
MSDS
Download (195 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAstrocytomas / Glioblastoma Multiforme (GBM) / Gliomas1
3CompletedTreatmentBrain and Central Nervous System Tumors3
3CompletedTreatmentBreast Cancer1
3CompletedTreatmentGlioblastoma Multiforme (GBM)1
3CompletedTreatmentGlioblastomas1
3CompletedTreatmentLeukemias / Malignant Lymphomas1
3CompletedTreatmentLeukemias / Neutropenia1
3CompletedTreatmentLymphoma, Large Cell, Diffuse1
3CompletedTreatmentMalignant Lymphomas5
3CompletedTreatmentMalignant Neoplasms of Eye, Brain and Other Parts of Central Nervous System1

Pharmacoeconomics

Manufacturers
  • Eisai inc
  • Bristol laboratories inc div bristol myers co
Packagers
  • Bristol-Myers Squibb Co.
  • Eisai Inc.
  • Mead Johnson and Co.
  • MGI Pharma
Dosage Forms
FormRouteStrength
KitIntravenous100 mg/30mL
Powder
Powder, for solutionIntravenous100 mg / vial
Injection, solution
Powder102 mg/1vial
Injection, powder, lyophilized, for solutionIntravenous100 mg
Injection, powder, for solutionParenteral
Powder, for solutionIntravenous
Injection, powder, for solutionIntravenous100 mg
ImplantIntralesional
WaferIntracavitary7.7 mg/1
WaferIntralesional7.7 mg
Wafer
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.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)31 °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-2.2ALOGPS
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

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

Drugtargets
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Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Other/unknown
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. 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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
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
Uniprot Name
Glutathione reductase, mitochondrial
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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  8. Puglia CD, Powell SR: Inhibition of cellular antioxidants: a possible mechanism of toxic cell injury. Environ Health Perspect. 1984 Aug;57:307-11. [Article]
Kind
Nucleotide
Organism
Humans
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. [Article]

Drug created on June 13, 2005 13:24 / Updated on July 24, 2021 14:57