| 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 |
|
| 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 |
|
| Toxicity |
Not Available |
