Temozolomide

Identification

Name
Temozolomide
Accession Number
DB00853
Description

Temozolomide (Temodar and Temodal) is an oral alkylating agent used for the treatment of refractory anaplastic astrocytoma -- a type of cancerous brain tumor. Temozolomide is not active until it is converted at physiologic pH to the active form, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC).

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 194.1508
Monoisotopic: 194.055223466
Chemical Formula
C6H6N6O2
Synonyms
  • 3-methyl-4-oxo-3,4-dihydroimidazo(5,1-d)(1,2,3,5)tetrazine-8-carboxamide
  • 3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxamide
  • 3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-as-tetrazine-8-carboxamide
  • 8-carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one
  • Methazolastone
  • Temozolodida
  • Temozolomid
  • Temozolomida
  • Témozolomide
  • Temozolomide
  • Temozolomidum
External IDs
  • BRN 5547136
  • CCRG 81045
  • CCRG-81045
  • M & B 39831
  • M&B 39831
  • M&B-39831
  • MK-7365
  • NSC 362856
  • NSC-362856
  • SCH 52365
  • SCH-52365

Pharmacology

Indication

For the treatment of adult patients diagnosed with anaplastic astrocytoma whose disease has progressed after therapy with nitrosourea and procarbazine, as well as concomitantly with radiation therapy for treatment of newly diagnosed glioblastoma multiforme. Also used as maintenance therapy for glioblastoma multiforme.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Temozolomide is an imidazotetrazine deritave and an antineoplastic agent. It is a prodrug that has little to no pharmacological activity until it is hydrolyzed in vivo to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC). After administration, temozolomide undergoes rapid, nonenzymatic hydrolysis at physiological pH to MTIC, which is the active form of the drug. MTIC is generated through the effect of water at the highly electropositive C4 position of temozolomide, causing the ring of temozolomide to open, release carbon dioxide, and generate MTIC.

Mechanism of action

Temozolomide is not active until it is converted at physiologic pH to MTIC. It is suggested that MTIC then alkylates DNA at the N7 position of guanine, O3 position of adenosine, and O6 position of guanosine, with the most common site being the N7 position. This methylation of guanine residues lead to single and double-strand DNA breaks and subsequent apoptotic cell death. It is suggested that the N7-methylguanine plays a critical role in the antitumor activity of the drug, as there is a correlation between the sensitivity of tumor cell lines to temozolomide and the activity of O6-alkylguanine alkyltransferase, which is the DNA repair protein that specifically removes alkyl groups at the O6 position of guanine. Cells lines that have lower levels of AGT are more sensitive to the cytotoxicity of temozolomide. It is also suggested that cytotoxic mechanism of temozolomide is related to the failure of the DNA MMR system to find a complementary base for methylated guanine. The DNA MMR system is involved in the formation of a number of proteins that remove methylated guanine. Evidence shows that when this repair process is targeted to the DNA strand opposite the O6-methylguanine, its inability to find the correct target leads to long-lived nicks in the DNA. The accumulation of these nicks lead to the inhibition of replication in the daughter cells, thereby blocking the cell cycle at the G2-M boundary.

TargetActionsOrganism
ADNA
cross-linking/alkylation
Humans
Absorption

Rapid and complete absorption in the gastrointestinal tract

Volume of distribution
  • 0.4 L/kg
Protein binding

15%

Metabolism
Not Available
Route of elimination

About 38% of the administered temozolomide total radioactive dose is recovered over 7 days: 37.7% in urine and 0.8% in feces.

Half-life

Approximately 1.8 hours.

Clearance
  • 5.5 L/hr/m2
Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
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
AbacavirTemozolomide may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbataceptThe risk or severity of adverse effects can be increased when Temozolomide is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Temozolomide.
AcarboseAcarbose may decrease the excretion rate of Temozolomide which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Temozolomide which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Temozolomide which could result in a higher serum level.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Temozolomide.
AcetaminophenAcetaminophen may decrease the excretion rate of Temozolomide which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Temozolomide which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Temozolomide which could result in a higher serum level.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take at the same time every day.
  • Take on an empty stomach. Food reduces the absorption of temozolomide and taking it on an empty stomach may reduce temozolomide associated nausea and vomiting.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Act TemozolomideCapsuleOralActavis Pharma CompanyNot applicableNot applicableCanada flag
Act TemozolomideCapsuleOralActavis Pharma Company2012-11-07Not applicableCanada flag
Act TemozolomideCapsuleOralActavis Pharma Company2015-12-08Not applicableCanada flag
Act TemozolomideCapsuleOralActavis Pharma Company2012-11-07Not applicableCanada flag
Act TemozolomideCapsuleOralActavis Pharma Company2012-11-07Not applicableCanada flag
Act TemozolomideCapsuleOralActavis Pharma Company2012-11-07Not applicableCanada flag
TemodalCapsule100 mgOralMerck Sharp & Dohme Limited1999-01-26Not applicableEU flag
TemodalCapsule5 mgOralMerck Sharp & Dohme Limited1999-01-26Not applicableEU flag
TemodalCapsule180 mgOralMerck Sharp & Dohme Limited1999-01-26Not applicableEU flag
TemodalCapsule100 mgOralMerck Ltd.1999-11-12Not applicableCanada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Ach-temozolomideCapsuleOralAccord Healthcare Inc2012-07-25Not applicableCanada flag
Ach-temozolomideCapsuleOralAccord Healthcare Inc2012-07-25Not applicableCanada flag
Ach-temozolomideCapsuleOralAccord Healthcare Inc2016-01-13Not applicableCanada flag
Ach-temozolomideCapsuleOralAccord Healthcare Inc2012-07-252020-02-05Canada flag
Ach-temozolomideCapsuleOralAccord Healthcare Inc2012-07-25Not applicableCanada flag
Ach-temozolomideCapsuleOralAccord Healthcare Inc2012-07-25Not applicableCanada flag
Apo-temozolomideCapsuleOralApotex CorporationNot applicableNot applicableCanada flag
Apo-temozolomideCapsuleOralApotex CorporationNot applicableNot applicableCanada flag
Apo-temozolomideCapsuleOralApotex CorporationNot applicableNot applicableCanada flag
Apo-temozolomideCapsuleOralApotex CorporationNot applicableNot applicableCanada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01AX03 — Temozolomide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as imidazotetrazines. These are organic polycyclic compounds containing an imidazole ring fused to a tetrazine ring. Imidazole is 5-membered ring consisting of three carbon atoms, and two nitrogen centers at the 1- and 3-positions. Tetrazine is a six-membered aromatic heterocycle made up of four nitrogen atoms and a two carbon atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Imidazotetrazines
Sub Class
Not Available
Direct Parent
Imidazotetrazines
Alternative Parents
2-heteroaryl carboxamides / Carbonylimidazoles / Tetrazines / N-substituted imidazoles / Vinylogous amides / Heteroaromatic compounds / Primary carboxylic acid amides / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds
show 3 more
Substituents
2-heteroaryl carboxamide / Aromatic heteropolycyclic compound / Azacycle / Azole / Carboxamide group / Carboxylic acid derivative / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Imidazole-4-carbonyl group
show 11 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
monocarboxylic acid amide, triazene derivative, imidazotetrazine (CHEBI:72564)

Chemical Identifiers

UNII
YF1K15M17Y
CAS number
85622-93-1
InChI Key
BPEGJWRSRHCHSN-UHFFFAOYSA-N
InChI
InChI=1S/C6H6N6O2/c1-11-6(14)12-2-8-3(4(7)13)5(12)9-10-11/h2H,1H3,(H2,7,13)
IUPAC Name
3-methyl-4-oxo-3H,4H-imidazo[4,3-d][1,2,3,5]tetrazine-8-carboxamide
SMILES
CN1N=NC2=C(N=CN2C1=O)C(N)=O

References

Synthesis Reference

Shen-Chun Kuo, "Synthesis of temozolomide and analogs." U.S. Patent US20020133006, issued September 19, 2002.

US20020133006
General References
  1. Neyns B, Tosoni A, Hwu WJ, Reardon DA: Dose-dense temozolomide regimens: antitumor activity, toxicity, and immunomodulatory effects. Cancer. 2010 Jun 15;116(12):2868-77. doi: 10.1002/cncr.25035. [PubMed:20564393]
  2. Wick W, Platten M, Weller M: New (alternative) temozolomide regimens for the treatment of glioma. Neuro Oncol. 2009 Feb;11(1):69-79. doi: 10.1215/15228517-2008-078. Epub 2008 Sep 4. [PubMed:18772354]
  3. Villano JL, Seery TE, Bressler LR: Temozolomide in malignant gliomas: current use and future targets. Cancer Chemother Pharmacol. 2009 Sep;64(4):647-55. doi: 10.1007/s00280-009-1050-5. Epub 2009 Jun 19. [PubMed:19543728]
  4. Meije Y, Lizasoain M, Garcia-Reyne A, Martinez P, Rodriguez V, Lopez-Medrano F, Juan RS, Lalueza A, Aguado JM: Emergence of cytomegalovirus disease in patients receiving temozolomide: report of two cases and literature review. Clin Infect Dis. 2010 Jun 15;50(12):e73-6. doi: 10.1086/653011. [PubMed:20455691]
  5. Trinh VA, Patel SP, Hwu WJ: The safety of temozolomide in the treatment of malignancies. Expert Opin Drug Saf. 2009 Jul;8(4):493-9. doi: 10.1517/14740330902918281 . [PubMed:19435405]
  6. Yung WK: Temozolomide in malignant gliomas. Semin Oncol. 2000 Jun;27(3 Suppl 6):27-34. [PubMed:10866347]
  7. Friedman HS, Kerby T, Calvert H: Temozolomide and treatment of malignant glioma. Clin Cancer Res. 2000 Jul;6(7):2585-97. [PubMed:10914698]
  8. Mutter N, Stupp R: Temozolomide: a milestone in neuro-oncology and beyond? Expert Rev Anticancer Ther. 2006 Aug;6(8):1187-204. [PubMed:16925485]
Human Metabolome Database
HMDB0014991
KEGG Drug
D06067
PubChem Compound
5394
PubChem Substance
46507934
ChemSpider
5201
BindingDB
50034562
RxNav
37776
ChEBI
72564
ChEMBL
CHEMBL810
ZINC
ZINC000001482184
Therapeutic Targets Database
DAP000987
PharmGKB
PA451609
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Temozolomide
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (67.2 KB)
MSDS
Download (58 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentBrain Neoplasms, Primary Malignant1
4CompletedTreatmentGlioblastomas1
4Not Yet RecruitingNot AvailableAdvanced Milignant Gliomas / Cytokine-Induced Killer Cells1
3Active Not RecruitingTreatmentBrain and Central Nervous System Tumors1
3Active Not RecruitingTreatmentBrain and Central Nervous System Tumors / Neurologic toxicity1
3Active Not RecruitingTreatmentBrain Cancer1
3Active Not RecruitingTreatmentEwing Family of Tumors / Ewing's Sarcoma (ES) / Ewing's Tumor Metastatic / Ewing's Tumor Recurrent / Metastatic Ewing's Sarcoma / Neoplasms / Neoplasms by Histologic Type / Neoplasms, Bone Tissue / Neoplasms, Connective and Soft Tissue / Neoplasms, Connective Tissue / Rare Diseases / Sarcomas1
3Active Not RecruitingTreatmentNeoplasms, Brain1
3CompletedTreatmentAdult Giant Cell Glioblastoma / Adult Glioblastoma / Adult Gliosarcoma / Cognitive Side Effects of Cancer Therapy / Glioblastomas / Gliosarcoma / Supratentorial Glioblastoma1
3CompletedTreatmentAnaplastic Astrocytoma (AA) / Glioblastomas1

Pharmacoeconomics

Manufacturers
  • Schering corp
  • Barr laboratories inc
Packagers
  • Baxter International Inc.
  • Physicians Total Care Inc.
  • Schering Corp.
  • Schering-Plough Inc.
  • University Of Iowa Pharmaceuticals
Dosage Forms
FormRouteStrength
Capsule100 mg
Capsule140 mg
Capsule180 mg
Capsule20 mg
Capsule250 mg
Capsule5 mg
Capsule, coatedOral5 mg
Capsule, coatedOral140 mg
Capsule, coatedOral250 mg
CapsuleNot applicable5 mg/1
CapsuleOral100 mg
CapsuleOral140 mg
CapsuleOral180 mg
CapsuleOral20 mg
CapsuleOral250 mg
CapsuleOral5 mg
Injection, powder, for solutionIntravenous2.5 mg/ml
Powder, for solutionIntravenous100 mg
Injection, powder, lyophilized, for solutionIntravenous100 mg
Injection2.5 mg/ml
CapsuleOral
Capsule, coatedOral20 mg
CapsuleOral100 mg/1
CapsuleOral180 mg/1
CapsuleOral20 mg/1
CapsuleOral250 mg/1
CapsuleOral5 mg/1
Injection, powder, lyophilized, for solutionIntravenous100 mg/40mL
Injection, powder, lyophilized, for solutionIntravenous2.5 mg/1mL
Powder1 kg/1kg
CapsuleNot applicable180 mg/1
CapsuleNot applicable20 mg/1
CapsuleNot applicable250 mg/1
CapsuleOral140 mg/1
CapsuleOral180 1/1
Capsule, coatedOral100 mg
Prices
Unit descriptionCostUnit
Temodar 250 mg capsule466.11USD capsule
Temodar 180 mg capsule401.53USD capsule
Temodar 100 mg capsule223.07USD capsule
Temodar 20 mg capsule44.62USD capsule
Temodar 5 mg capsule10.84USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5260291No1993-11-092013-08-11US flag
CA2476494No2010-04-272023-02-20Canada flag
CA2066313No2002-08-202012-04-16Canada flag
US6987108No2006-01-172023-09-08US flag
US7786118No2010-08-312023-02-21US flag
US8623868No2014-01-072023-02-21US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)212 °CNot Available
logP-2.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility5.09 mg/mLALOGPS
logP-1ALOGPS
logP-0.28ChemAxon
logS-1.6ALOGPS
pKa (Strongest Acidic)10.51ChemAxon
pKa (Strongest Basic)-3.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area105.94 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity47.86 m3·mol-1ChemAxon
Polarizability16.88 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9879
Caco-2 permeable+0.5608
P-glycoprotein substrateNon-substrate0.7228
P-glycoprotein inhibitor INon-inhibitor0.9255
P-glycoprotein inhibitor IINon-inhibitor0.9823
Renal organic cation transporterNon-inhibitor0.8822
CYP450 2C9 substrateNon-substrate0.7948
CYP450 2D6 substrateNon-substrate0.8695
CYP450 3A4 substrateNon-substrate0.5855
CYP450 1A2 substrateNon-inhibitor0.8134
CYP450 2C9 inhibitorNon-inhibitor0.9753
CYP450 2D6 inhibitorNon-inhibitor0.9479
CYP450 2C19 inhibitorNon-inhibitor0.9522
CYP450 3A4 inhibitorNon-inhibitor0.9571
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9954
Ames testNon AMES toxic0.5322
CarcinogenicityNon-carcinogens0.9412
BiodegradationNot ready biodegradable0.5172
Rat acute toxicity2.5279 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7553
hERG inhibition (predictor II)Non-inhibitor0.9242
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

Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Cross-linking/alkylation
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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  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:17016423]
  3. Zaremba T, Curtin NJ: PARP inhibitor development for systemic cancer targeting. Anticancer Agents Med Chem. 2007 Sep;7(5):515-23. [PubMed:17896912]
  4. Dinca EB, Sarkaria JN, Schroeder MA, Carlson BL, Voicu R, Gupta N, Berger MS, James CD: Bioluminescence monitoring of intracranial glioblastoma xenograft: response to primary and salvage temozolomide therapy. J Neurosurg. 2007 Sep;107(3):610-6. [PubMed:17886562]
  5. Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L: Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol Res. 2007 Oct;56(4):275-87. Epub 2007 Aug 9. [PubMed:17897837]
  6. Neyns B, Tosoni A, Hwu WJ, Reardon DA: Dose-dense temozolomide regimens: antitumor activity, toxicity, and immunomodulatory effects. Cancer. 2010 Jun 15;116(12):2868-77. doi: 10.1002/cncr.25035. [PubMed:20564393]
  7. Wick W, Platten M, Weller M: New (alternative) temozolomide regimens for the treatment of glioma. Neuro Oncol. 2009 Feb;11(1):69-79. doi: 10.1215/15228517-2008-078. Epub 2008 Sep 4. [PubMed:18772354]
  8. Natelson EA, Pyatt D: Temozolomide-induced myelodysplasia. Adv Hematol. 2010;2010:760402. doi: 10.1155/2010/760402. Epub 2010 Mar 4. [PubMed:20224797]
  9. Friedman HS, Kerby T, Calvert H: Temozolomide and treatment of malignant glioma. Clin Cancer Res. 2000 Jul;6(7):2585-97. [PubMed:10914698]

Drug created on June 13, 2005 07:24 / Updated on September 25, 2020 15:13

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