Identification

Name
Temozolomide
Accession Number
DB00853
Description

Refractory anaplastic astrocytoma (WHO grade III) and Glioblastoma multiforme (WHO grade IV) are primary malignant brain tumours with poor prognosis and limited treatment options. Despite considerable genetic heterogeneity, these tumours often have impaired DNA repair systems, rendering them initially sensitive to alkylating agents, although they invariably develop resistance to these agents over time.9,11,17 Temozolomide is an imidazotetrazine prodrug that is stable at acidic pH but undergoes spontaneous nonenzymatic hydrolysis at neutral or slightly basic pH; these properties allow for both oral and intravenous administration.10,13,16,17 Following initial hydrolysis, further reactions liberate a highly reactive methyl diazonium cation capable of methylating various residues on adenosine and guanine bases leading to DNA lesions and eventual apoptosis.10,16 Temozomolide as an adjunct to radiotherapy followed by maintenance dosing remains the standard of care for both Glioblastoma and refractory anaplastic astrocytoma.17

Temozolomide was granted FDA approval on August 11, 1999, as an oral capsule and subsequently on February 27, 2009, as an intravenous injection. It is currently marketed under the trademark TEMODAR® by Merck.17

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

Pharmacology
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Indication

Temozolomide is indicated in adult patients for the treatment of newly diagnosed glioblastoma concomitantly with radiotherapy and for use as maintenance treatment thereafter. It is also indicated for the treatment of refractory anaplastic astrocytoma in adult patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.17

Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH in vivo to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death. Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients. Patients must have an ANC of ≥1.5 x 109/L and a platelet count of ≥100 x 109/L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and 22 of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages. Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose. Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, respectively.17

Mechanism of action

Glioblastoma (glioblastoma multiforme) is the most common and aggressive adult primary brain tumour, accounting for 45.6% of all primary malignant brain tumours. Primarily defined histopathologically by necrosis and microvascular proliferation (WHO grade IV classification), glioblastomas are commonly treated through radiotherapy and concomitant alkylation-based chemotherapy with temozolomide.9 Temozolomide (TMZ) is a small (194 Da) lipophilic alkylating agent of the imidazotetrazine class that is stable at acidic pH, allowing for both oral and intravenous dosing, and can cross the blood-brain barrier to affect CNS tumours.10,11,17,15 After absorption, TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation.10 Brain tumours such as glioblastoma typically possess a more alkaline pH than healthy tissue, favouring TMZ activation within tumour tissue.10

The methyl diazonium cation is highly reactive and methylates DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). Although more prevalent, N7-MeG and N3-MeA are rapidly repaired by the base excision repair pathway and are not primary mediators of temozolomide toxicity, although N3-MeA lesions are lethal if not repaired. By comparison, repair of O6-MeG requires action by the suicide enzyme methylguanine-DNA methyltransferase (MGMT), which removes the methyl group to restore guanine. If not repaired by MGMT, O6-MeG mispairs with thymine, activating the DNA mismatch repair (MMR) pathway that removes the thymine (not the O6-MeG), resulting in futile cycles of repair and eventual DNA strand breaks leading to apoptosis.10 As MMR activity is crucial for temozolomide cytotoxicity, cells that have reduced or absent MGMT function and an intact MMR pathway are the most sensitive to temozolomide treatment.10,11 Glioblastomas that upregulate MGMT downregulate MMR or alter both are resistant to TMZ, leading to treatment failure.10

More recently, increased interest has also been shown in the immunomodulatory effects of TMZ, related to its myelosuppressive effects. Counterintuitively, lymphodepletion may enhance the antitumour effects of cellular immunotherapy and improve the dynamics of memory cells by altering tumour-specific versus tumour-tolerant populations. The depletion of tumour-localized immunosuppressive Treg cells may contribute to an improved response to immunotherapy. Hence, TMZ treatment may also form the backbone of immunotherapy strategies against glioblastoma in the future.12

TargetActionsOrganism
ADNA
cross-linking/alkylation
Humans
Absorption

Temozolomide is rapidly and completely absorbed in the gastrointestinal tract and is stable at both acidic and neutral pH. Therefore, temozolomide may be administered both orally and intravenously with a median Tmax of one hour. Following a single oral dose of 150 mg/m2, temozolomide and its active MTIC metabolite had Cmax values of 7.5 μg/mL and 7.5 μg/mL and AUC values of 23.4 μg*hr/mL and 864 ng*hr/mL, respectively. Similarly, following a single 90-minute IV infusion of 150 mg/m2, temozolide and its active MTIC metabolite had Cmax values of 7.3 μg/mL and 276 ng/mL and AUC values of 24.6 μg*hr/mL and 891 ng*hr/mL, respectively. Temozolomide kinetics are linear over the range of 75-250 mg/m2/day.17

Oral temozolomide absorption is affected by food. Administration following a high-fat breakfast of 587 calories caused the mean Cmax and AUC to decrease by 32% and 9%, respectively, and the median Tmax to increase by 2-fold (from 1-2.25 hours).17

Volume of distribution

Temozolomide has a mean apparent volume of distribution (%CV) of 0.4 (13%) L/kg.17

Protein binding

Temozolomide plasma protein binding varies from 8-36%, with an average of around 15%.13,17 In vitro binding experiments revealed approximate dissociation constants of 0.2-0.25 and 0.12 mM for temozolomide with human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), respectively; despite the slightly higher affinity for AGP, it is likely that temozolomide is predominantly bound to HSA due to its higher serum concentration. In addition, temozolomide binding to HSA results in delayed hydrolysis and a longer half-life than in buffer (1 versus 1.8 hours).14

Metabolism

After absorption, temozolomide undergoes nonenzymatic chemical conversion to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) plus carbon dioxide and to a temozolomide acid metabolite, which occurs at physiological pH but is enhanced with increasing alkalinity.10,13,16 MTIC subsequently reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation, the active alkylating species.10,13,16 The cytochrome P450 system plays only a minor role in temozolomide metabolism. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively.17

Hover over products below to view reaction partners

Route of elimination

Roughly 38% of administered temozolomide can be recovered over seven days, with 38% in the urine and only 0.8% in the feces. The recovered material comprises mainly metabolites: unidentified polar metabolites (17%), AIC (12%), and the temozolomide acid metabolite (2.3%). Only 6% of the recovered dose represents unchanged temozolomide.17

Half-life

Temozolomide has a mean elimination half-life of 1.8 hours.17

Clearance

Temozolomide has a clearance of approximately 5.5 L/hr/m2.17

Adverse Effects
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Toxicity

The primary dose-limiting toxicity of temozolomide is myelosuppression, which can occur with any dose but is more severe at higher doses. Patients taking high doses experienced adverse reactions, including severe and prolonged myelosuppression, infections, and death. One patient who took 2000 mg/day for five days experienced pancytopenia, pyrexia, and multi-organ failure, which resulted in death. Patients experiencing an overdose should have complete blood counts monitored and provided with supportive care as necessary.17

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.
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.
AclidiniumTemozolomide may decrease the excretion rate of Aclidinium which could result in a higher serum level.
Interactions
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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

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Act TemozolomideCapsuleOralTEVA Canada LimitedNot applicableNot applicableCanada flag
Act TemozolomideCapsuleOralTEVA Canada Limited2012-11-07Not applicableCanada flag
Act TemozolomideCapsuleOralTEVA Canada Limited2015-12-08Not applicableCanada flag
Act TemozolomideCapsuleOralTEVA Canada Limited2012-11-07Not applicableCanada flag
Act TemozolomideCapsuleOralTEVA Canada Limited2012-11-07Not applicableCanada flag
Act TemozolomideCapsuleOralTEVA Canada Limited2012-11-07Not applicableCanada flag
Emozolomide AccordCapsuleOralAccord Healthcare S.L.U.2016-09-08Not applicableEU flag
Emozolomide AccordCapsuleOralAccord Healthcare S.L.U.2016-09-08Not applicableEU flag
Emozolomide AccordCapsuleOralAccord Healthcare S.L.U.2016-09-08Not applicableEU flag
Emozolomide AccordCapsuleOralAccord Healthcare S.L.U.2016-09-08Not applicableEU flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
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
Ach-temozolomideCapsuleOralAccord Healthcare Inc2016-01-13Not applicableCanada 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

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]
  9. Wirsching HG, Galanis E, Weller M: Glioblastoma. Handb Clin Neurol. 2016;134:381-97. doi: 10.1016/B978-0-12-802997-8.00023-2. [PubMed:26948367]
  10. Zhang J, Stevens MF, Bradshaw TD: Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012 Jan;5(1):102-14. doi: 10.2174/1874467211205010102. [PubMed:22122467]
  11. Thomas A, Tanaka M, Trepel J, Reinhold WC, Rajapakse VN, Pommier Y: Temozolomide in the Era of Precision Medicine. Cancer Res. 2017 Feb 15;77(4):823-826. doi: 10.1158/0008-5472.CAN-16-2983. Epub 2017 Feb 3. [PubMed:28159862]
  12. Karachi A, Dastmalchi F, Mitchell DA, Rahman M: Temozolomide for immunomodulation in the treatment of glioblastoma. Neuro Oncol. 2018 Nov 12;20(12):1566-1572. doi: 10.1093/neuonc/noy072. [PubMed:29733389]
  13. Baker SD, Wirth M, Statkevich P, Reidenberg P, Alton K, Sartorius SE, Dugan M, Cutler D, Batra V, Grochow LB, Donehower RC, Rowinsky EK: Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res. 1999 Feb;5(2):309-17. [PubMed:10037179]
  14. Rubio-Camacho M, Encinar JA, Martinez-Tome MJ, Esquembre R, Mateo CR: The Interaction of Temozolomide with Blood Components Suggests the Potential Use of Human Serum Albumin as a Biomimetic Carrier for the Drug. Biomolecules. 2020 Jul 9;10(7). pii: biom10071015. doi: 10.3390/biom10071015. [PubMed:32659914]
  15. de Gooijer MC, de Vries NA, Buckle T, Buil LCM, Beijnen JH, Boogerd W, van Tellingen O: Improved Brain Penetration and Antitumor Efficacy of Temozolomide by Inhibition of ABCB1 and ABCG2. Neoplasia. 2018 Jul;20(7):710-720. doi: 10.1016/j.neo.2018.05.001. Epub 2018 May 28. [PubMed:29852323]
  16. Denny BJ, Wheelhouse RT, Stevens MF, Tsang LL, Slack JA: NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry. 1994 Aug 9;33(31):9045-51. doi: 10.1021/bi00197a003. [PubMed:8049205]
  17. FDA Approved Drug Products: TEMODAR (temozolomide) capsules and injection [Link]
  18. Cayman Chemical: temozolomide MSDS [Link]
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 / 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
3Active Not RecruitingTreatmentNewly Diagnosed 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
Capsule, coatedOral
CapsuleNot applicable5 mg/1
CapsuleOral180 mg
Injection, powder, for solutionIntravenous
Powder, for solutionIntravenous100 mg
Injection, powder, lyophilized, for solutionIntravenous
CapsuleOral
InjectionParenteral
Capsule, coatedOral100 mg
Capsule, coatedOral250 mg
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
CapsuleOral100 mg
CapsuleOral20 mg
CapsuleOral250 mg
CapsuleOral5 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

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)212 °Chttp://www.chemspider.com/Chemical-Structure.5201.html
water solubility5.09 g/Lhttps://hmdb.ca/metabolites/HMDB0014991
logP-1.153https://www.ema.europa.eu/en/documents/assessment-report/temomedac-epar-public-assessment-report_en.pdf
Predicted Properties
PropertyValueSource
logP-0.28ChemAxon
pKa (Strongest Acidic)10.46ChemAxon
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

Drugtargets
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Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Cross-linking/alkylation
Curator comments
Temozolomide spontaneously hydrolyzes to active metabolites that methylate DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). The O6-MeG alkylation is thought to be the primary modification responsible for temozolomide's mechanism of action.
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. Zaremba T, Curtin NJ: PARP inhibitor development for systemic cancer targeting. Anticancer Agents Med Chem. 2007 Sep;7(5):515-23. [PubMed:17896912]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. Natelson EA, Pyatt D: Temozolomide-induced myelodysplasia. Adv Hematol. 2010;2010:760402. doi: 10.1155/2010/760402. Epub 2010 Mar 4. [PubMed:20224797]
  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. Zhang J, Stevens MF, Bradshaw TD: Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012 Jan;5(1):102-14. doi: 10.2174/1874467211205010102. [PubMed:22122467]
  9. FDA Approved Drug Products: TEMODAR (temozolomide) capsules and injection [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
Curator comments
In vitro experiments suggest that temozolomide binding to human serum albumin (HSA) has a Ka of ~4000-5100 M^-1 (Kd of ~0.2-0.25 mM) and that HSA is the main plasma protein binding temozolomide under physiological conditions.
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Rubio-Camacho M, Encinar JA, Martinez-Tome MJ, Esquembre R, Mateo CR: The Interaction of Temozolomide with Blood Components Suggests the Potential Use of Human Serum Albumin as a Biomimetic Carrier for the Drug. Biomolecules. 2020 Jul 9;10(7). pii: biom10071015. doi: 10.3390/biom10071015. [PubMed:32659914]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
Curator comments
In vitro experiments suggest that temozolomide binding to alpha-1-acid glycoprotein (AGP) has a Ka of 8184 ± 983 M^-1 (Kd of ~0.12 mM), but that due to typical AGP plasma concentrations, AGP binding represents a small fraction of total temozolomide protein binding under physiological conditions.
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Rubio-Camacho M, Encinar JA, Martinez-Tome MJ, Esquembre R, Mateo CR: The Interaction of Temozolomide with Blood Components Suggests the Potential Use of Human Serum Albumin as a Biomimetic Carrier for the Drug. Biomolecules. 2020 Jul 9;10(7). pii: biom10071015. doi: 10.3390/biom10071015. [PubMed:32659914]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Inhibition of P-glycoprotein and BCRP increases brain penetration of temozolomide, suggesting that these transporters are key mediators of temozolomide efflux.
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. de Gooijer MC, de Vries NA, Buckle T, Buil LCM, Beijnen JH, Boogerd W, van Tellingen O: Improved Brain Penetration and Antitumor Efficacy of Temozolomide by Inhibition of ABCB1 and ABCG2. Neoplasia. 2018 Jul;20(7):710-720. doi: 10.1016/j.neo.2018.05.001. Epub 2018 May 28. [PubMed:29852323]
  2. Lin F, de Gooijer MC, Roig EM, Buil LC, Christner SM, Beumer JH, Wurdinger T, Beijnen JH, van Tellingen O: ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin Cancer Res. 2014 May 15;20(10):2703-13. doi: 10.1158/1078-0432.CCR-14-0084. Epub 2014 Mar 19. [PubMed:24647572]
  3. Munoz JL, Walker ND, Scotto KW, Rameshwar P: Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells. Cancer Lett. 2015 Oct 10;367(1):69-75. doi: 10.1016/j.canlet.2015.07.013. Epub 2015 Jul 21. [PubMed:26208431]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Inhibition of P-glycoprotein and BCRP increases brain penetration of temozolomide, suggesting that these transporters are key mediators of temozolomide efflux.
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. de Gooijer MC, de Vries NA, Buckle T, Buil LCM, Beijnen JH, Boogerd W, van Tellingen O: Improved Brain Penetration and Antitumor Efficacy of Temozolomide by Inhibition of ABCB1 and ABCG2. Neoplasia. 2018 Jul;20(7):710-720. doi: 10.1016/j.neo.2018.05.001. Epub 2018 May 28. [PubMed:29852323]
  2. Lin F, de Gooijer MC, Roig EM, Buil LC, Christner SM, Beumer JH, Wurdinger T, Beijnen JH, van Tellingen O: ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin Cancer Res. 2014 May 15;20(10):2703-13. doi: 10.1158/1078-0432.CCR-14-0084. Epub 2014 Mar 19. [PubMed:24647572]

Drug created on June 13, 2005 13:24 / Updated on April 23, 2021 04:04