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药品详细

Temozolomide(替莫唑胺)

化学结构式图
中文名
替莫唑胺
英文名
Temozolomide
分子式
C6H6N6O2
化学名
3-methyl-4-oxo-3H,4H-imidazo[4,3-d][1,2,3,5]tetrazine-8-carboxamide
分子量
Average: 194.1508
Monoisotopic: 194.055223466
CAS号
85622-93-1
ATC分类
L01A 烷化剂
药物类型
small molecule
阶段
approved
商品名
Temodal;Temodar;
同义名
Methazolastone;Temozolamide;Temozolodida [Spanish];temozolomide;Temozolomidum [Latin];
基本介绍

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).

生产厂家
  • Barr laboratories inc
  • Schering corp
封装厂家
参考
Synthesis Reference Not Available
General Reference
  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. Pubmed
  2. Wick W, Platten M, Weller M: New (alternative) temozolomide regimens for the treatment of glioma. Neuro Oncol. 2009 Feb;11(1):69-79. Epub 2008 Sep 4. Pubmed
  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. Epub 2009 Jun 19. Pubmed
  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. Pubmed
  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. Pubmed
  6. Yung WK: Temozolomide in malignant gliomas. Semin Oncol. 2000 Jun;27(3 Suppl 6):27-34. Pubmed
  7. Friedman HS, Kerby T, Calvert H: Temozolomide and treatment of malignant glioma. Clin Cancer Res. 2000 Jul;6(7):2585-97. Pubmed
  8. Mutter N, Stupp R: Temozolomide: a milestone in neuro-oncology and beyond? Expert Rev Anticancer Ther. 2006 Aug;6(8):1187-204. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Tetrazines
Substructures
  • Amino Ketones
  • Tetrazines
  • Carbamates and Derivatives
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Imines
  • Carboxylic Acids and Derivatives
  • Cyanamides
适应症
Cancer 癌症;
药理
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.
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.
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
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
melting point 212 °C Not Available
logP -2.8 Not Available
Predicted Properties
Property Value Source
water solubility 5.09e+00 g/l ALOGPS
logP -1 ALOGPS
logP -0.28 ChemAxon
logS -1.6 ALOGPS
pKa (strongest acidic) 10.51 ChemAxon
pKa (strongest basic) -3.6 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 105.94 ChemAxon
rotatable bond count 1 ChemAxon
refractivity 47.86 ChemAxon
polarizability 16.88 ChemAxon
药物相互作用
Drug Interaction
Natalizumab The immunosuppressant, Temozolomide, may increase the adverse effects of Natalizumab. Increased risk of Progressive Multifocal Leukoencephalopathy (PML) and other infections. Concurrent therapy should be avoided.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
食物相互作用
Not Available

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