Mechanism of action The therapeutic benefit of<unk>  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<unk> , 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<unk> . Conversely, the presence of AGT protein in brain tumors predicts poor response to<unk>  and these patients receive little benefit from chemotherapy with<unk> . Pharmacokinetics<unk>  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.<unk>  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<unk>  acid and unidentified hydrophilic substances. Plasma half-life is 1.8 hours. The substance and its metabolites are mainly excreted via the urine. File:MTIC skeletal.MTIC, the active metabolite File:5-aminoimidazole-4-carboxamide.AIC (part of the naturally occurring AICA ribonucleotide) File:Dacarbazine.The related drug dacarbazine for comparison
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