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Identification
NameLomustine
Accession NumberDB01206  (APRD00292)
Typesmall molecule
Groupsapproved
Description

An alkylating agent of value against both hematologic malignancies and solid tumors. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
CCNUNot AvailableNot Available
ChloroethylcyclohexylnitrosoureaNot AvailableNot Available
LomustinaSpanishINN
LomustinumLatinINN
SaltsNot Available
Brand names
NameCompany
BelustineNot Available
CecenuNot Available
CeeNUNot Available
CINUNot Available
Brand mixturesNot Available
Categories
CAS number13010-47-4
WeightAverage: 233.695
Monoisotopic: 233.093104478
Chemical FormulaC9H16ClN3O2
InChI KeyInChIKey=GQYIWUVLTXOXAJ-UHFFFAOYSA-N
InChI
InChI=1S/C9H16ClN3O2/c10-6-7-13(12-15)9(14)11-8-4-2-1-3-5-8/h8H,1-7H2,(H,11,14)
IUPAC Name
3-(2-chloroethyl)-1-cyclohexyl-3-nitrosourea
SMILES
ClCCN(N=O)C(=O)NC1CCCCC1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganonitrogen Compounds
ClassHydrazines and Derivatives
SubclassSemicarbazides
Direct parentSemicarbazides
Alternative parentsPolyamines; Organochlorides; Alkyl Chlorides
Substituentspolyamine; organochloride; amine; organohalogen; alkyl halide; alkyl chloride
Classification descriptionThis compound belongs to the semicarbazides. These are organic compounds containing the semicarbazide functional grou with the general structure R1(N)R2NR3C(=O)N(R4)R5 (R1-R5=H,alkyl,aryl), a derivative of urea, where the amine group on one side has been replace by an hydrazine group.
Pharmacology
IndicationFor the treatment of primary and metastatic brain tumors as a component of combination chemotherapy in addition to appropriate surgical and/or radiotherapeutic procedures. Also used in combination with other agents as secondary therapy for the treatment of refractory or relapsed Hodgkin's disease.
PharmacodynamicsLomustine is an alkylating agent of the nitrosourea type. Lomustine and its metabolites interferes with the function of DNA and RNA. It is cell cycle–phase nonspecific. Cancers form when some cells within the body multiply uncontrollably and abnormally. These cells then spread and destroy nearby tissues. Lomustine acts by slowing this process down. It kills cancer cells by damaging the DNA (the genetic material inside the cells) and stops them from dividing.
Mechanism of actionLomustine is a highly lipophilic nitrosourea compound which undergoes hydrolysis in vivo to form reactive metabolites. These metabolites cause alkylation and cross-linking of DNA (at the O6 position of guanine-containing bases) and RNA, thus inducing cytotoxicity. Other biologic effects include inhibition of DNA synthesis and some cell cycle phase specificity. Nitrosureas generally lack cross-resistance with other alkylating agents. As lomustine is a nitrosurea, it may also inhibit several key processes such as carbamoylation and modification of cellular proteins.
AbsorptionWell and rapidly absorbed from the gastrointestinal tract.
Volume of distributionNot Available
Protein binding50%
Metabolism

Hepatic. Rapid and complete, with active metabolites.

Route of eliminationFollowing oral administration of radioactive CeeNU at doses ranging from 30 mg/m2 to 100 mg/m2, about half of the radioactivity given was excreted in the urine in the form of degradation products within 24 hours.
Half lifeApproximately 94 minutes, however the metabolites have a serum half-life of 16 to 48 hours.
ClearanceNot Available
ToxicityOral, rat: LD50 = 70 mg/kg. Pulmonary toxicity has been reported at cumulative doses usually greater than 1,100 mg/m2. There is one report of pulmonary toxicity at a cumulative dose of only 600 mg. The onset of toxicity has varied from 6 months after initiation of therapy, to as late as 15 years after.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9962
Blood Brain Barrier + 0.9383
Caco-2 permeable - 0.5443
P-glycoprotein substrate Non-substrate 0.6803
P-glycoprotein inhibitor I Non-inhibitor 0.837
P-glycoprotein inhibitor II Non-inhibitor 0.8642
Renal organic cation transporter Non-inhibitor 0.7664
CYP450 2C9 substrate Non-substrate 0.763
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.651
CYP450 1A2 substrate Non-inhibitor 0.8127
CYP450 2C9 substrate Non-inhibitor 0.829
CYP450 2D6 substrate Non-inhibitor 0.9159
CYP450 2C19 substrate Non-inhibitor 0.7446
CYP450 3A4 substrate Non-inhibitor 0.8499
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.789
Ames test AMES toxic 0.9309
Carcinogenicity Carcinogens 0.5074
Biodegradation Not ready biodegradable 0.7517
Rat acute toxicity 3.5549 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.8183
hERG inhibition (predictor II) Non-inhibitor 0.8735
Pharmacoeconomics
Manufacturers
  • Bristol myers squibb co
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
Prices
Unit descriptionCostUnit
Ceenu 100 mg capsule60.61USDcapsule
Ceenu 40 mg capsule31.88USDcapsule
CeeNU 300 mg capsule31.69USDcapsule
Ceenu dose pack30.47USDeach
Ceenu 10 mg capsule10.77USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point88-90 °CPhysProp
water solubility111 mg/LNot Available
logP2.83HANSCH,C & LEO,AJ (1985)
Predicted Properties
PropertyValueSource
water solubility7.55e-01 g/lALOGPS
logP2.62ALOGPS
logP2.16ChemAxon
logS-2.5ALOGPS
pKa (strongest acidic)13.3ChemAxon
pKa (strongest basic)-5.3ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count2ChemAxon
hydrogen donor count1ChemAxon
polar surface area61.77ChemAxon
rotatable bond count4ChemAxon
refractivity58.65ChemAxon
polarizability23.61ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00363
PubChem Compound3950
PubChem Substance46506562
ChemSpider3813
Therapeutic Targets DatabaseDAP000991
PharmGKBPA164749407
Drug Product Database360414
RxListhttp://www.rxlist.com/cgi/generic2/lomustine.htm
Drugs.comhttp://www.drugs.com/cdi/lomustine-ccnu.html
WikipediaLomustine
ATC CodesL01AD02
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(56.6 KB)
Interactions
Drug Interactions
Drug
AtomoxetineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
BendamustineIncreases toxicity through pharmacodynamic synergism. Additive myelosuppression.
TerbinafineTerbinafine may reduce the metabolism and clearance of Lomustine. Consider alternate therapy or monitor for therapeutic/adverse effects of Lomustine if Terbinafine is initiated, discontinued or dose changed.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food InteractionsNot Available

1. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: cross-linking/alkylation

Components

Name UniProt ID Details

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. Larkin JM, Hughes SA, Beirne DA, Patel PM, Gibbens IM, Bate SC, Thomas K, Eisen TG, Gore ME: A phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma. Br J Cancer. 2007 Jan 15;96(1):44-8. Epub 2006 Dec 5. Pubmed
  4. Spiro T, Liu L, Gerson S: New cytotoxic agents for the treatment of metastatic malignant melanoma: temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance. Forum (Genova). 2000 Jul-Sep;10(3):274-85. Pubmed

2. Stathmin-4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Stathmin-4 Q9H169 Details

References:

  1. Liang XJ, Choi Y, Sackett DL, Park JK: Nitrosoureas inhibit the stathmin-mediated migration and invasion of malignant glioma cells. Cancer Res. 2008 Jul 1;68(13):5267-72. Pubmed
  2. Wu WW, Wang G, Liang XJ, Park JK, Shen RF: Covalent modification of stathmin by CCNU determined by FTMS analysis of modified proteins and tryptic peptides. Biochem Biophys Res Commun. 2008 Feb 29;367(1):7-13. Epub 2007 Dec 26. Pubmed

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

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 September 16, 2013 17:13