Temozolomide is a prodrug; it is spontaneously hydrolyzed at physiological pH to 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC), which further splits into monomethylhydrazine, likely the active methylating agent, and 5-aminoimidazole-4-carboxamide (AIC). Other metabolites include temozolomide acid and unidentified hydrophilic substances.Plasma half-life is 1.8 hours. The substance and its metabolites are mainly excreted via the urine. Chemical properties
Temozolomide is an imidazotetrazine derivative. It is slightly soluble in water and aqueous acids, and decomposes at 212 °C (414 °F). It was recently discovered that temozolomide is an explosive, tentatively assigned as UN Class 1.Mirroring its medicinal use as an alkylating antineoplastic agent, temozolomide has been reported to be a comparatively safe and stable in situ source of diazomethane in organic synthesis. In particular, its use as a methylating and cyclopropanating reagent was demonstrated. History
The agent was discovered by Simon Langdon, Niel Gibson and John Hickman at Aston University in Birmingham, England. The molecule was synthesised by PhD student Robert Stone, in a project directed by Malcolm Stevens to find anti-allergens. Its preclinical activity was reported in 1987 in Cancer Research. Stevens then directed its development with the late Edward Newlands at Charing Cross Hospital.It was approved for medical use in the European Union in January 1999, and in the United States in August 1999. The intravenous formulation was approved in the United States in February 2009. Research
Laboratory studies and clinical trials have started investigating the possibility of increasing the anticancer potency of temozolomide by combining it with other pharmacologic agents.
Interactions
As temozolomide is not metabolized in the liver and has a low affinity to plasma proteins, it is expected to have a low potential for interactions. An analysis of patient data showed no interactions with a range of other drugs; the exception is valproic acid, which slightly slows down temozolomide elimination from the body. Combining the drug with other myelosuppressants may increase the risk of myelosuppression. Pharmacology
Mechanism of action
The therapeutic benefit of temozolomide depends on its ability to alkylate/methylate DNA, which most often occurs at the N-7 or O-6 positions of guanine residues. This methylation damages the DNA and triggers the death of tumor cells. However, some tumor cells are able to repair this type of DNA damage, and therefore diminish the therapeutic efficacy of temozolomide, by expressing a protein O6-alkylguanine DNA alkyltransferase (AGT) encoded in humans by the O-6-methylguanine-DNA methyltransferase (MGMT) gene. In some tumors, epigenetic silencing of the MGMT gene prevents the synthesis of this enzyme, and as a consequence such tumors are more sensitive to killing by temozolomide. Conversely, the presence of AGT protein in brain tumors predicts poor response to temozolomide and these patients receive little benefit from chemotherapy with temozolomide. Pharmacokinetics
Temozolomide is quickly and almost completely absorbed from the gut, and readily penetrates the blood–brain barrier; the concentration in the cerebrospinal fluid is 30% of the concentration in the blood plasma. Intake with food decreases maximal plasma concentrations by 33% and the area under the curve by 9%. Only 15% (10–20%) of the substance are bound to blood plasma proteins.