Disposition and pharmacokinetics of temozolomide in rat

Abstract

1. Temozolomide, an imidazotetrazine derivative, is a cytotoxic alkylating agent of broad-spectrum antitumour activity. The absorption, metabolism, distribution and excretion of temozolomide have been investigated in male and female Sprague-Dawley and Long-Evans rats following single oral or intravenous dose administration of 200 mg m(-2) non-radiolabelled or (14)C-radiolabelled temozolomide. The distribution of (14)C-temozolomide was also evaluated by whole-body autoradiography in male Sprague-Dawley rats. Plasma concentrations of temozolomide and its active metabolite 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection. Plasma, urine and faeces were profiled by HPLC with radiochemical detection. 2. Temozolomide was rapidly and extensively (>90%) absorbed and widely distributed in tissues. The distribution pattern of radioactivity was gender independent. Penetration into the brain following oral or intravenous administration was 35-39% based on the brain/plasma AUC ratio. 3. Following intravenous or oral administration, temozolomide was primarily eliminated renally (75-85% of the dose) as either unchanged drug, a carboxylic acid analogue, AIC (a degradation product) and a highly polar unidentified peak. Biliary excretion was minimal (1.4-1.6%). The pharmacokinetics (oral versus intravenous) were similar and gender independent. The absolute oral availability was 96-100%. Temozolomide was rapidly eliminated (t(1/2) = 1.2 h) and converted to MTIC. 4. Systemic exposure to MTIC was about 2% that of temozolomide. Overall, the disposition of temozolomide in rats was similar to that observed in humans.

Modulation of KCa channels increases anticancer drug delivery to brain tumors and prolongs survival in xenograft model

“…39,40 The differential level of drug entry in tumor and area surrounding tumor may also be due to different degree of angiogenesis. The QAR method, however, offered a unique opportunity to test whether the [ 14 C]-TMZ has entered brain tumor by crossing the BTB, as opposed to TMZ disposition and pharmacokinetic study, 41 which were based on brain/ plasma AUC (area under the curve) ratio following i.v. infusion.…”

Temozolomide and Other Potential Agents for the Treatment of Glioblastoma Multiforme

“…MTIC in turn decomposes into 4-amino-5-imidazole-carboxamide (AIC) 27,28 in acidic environments. 26,[29][30][31][32][33] By oral administration, mean maximum peak is at 1.2 hours and mean half-life is 1.9 hours. 29 For patients who have absorption difficulties, nausea, or are too young to swallow TMZ in pill form, intravenous TMZ is an alternative 34 that is biologically equivalent to oral TMZ, with nearly identical pharmacokinetic parameters (half-life, time of maximum peak, and clearance).…”

“…However, some AIC may remain in the body to be used as an intermediate in purine synthesis. [27][28][29][30] Although the blood-brain barrier may be an obstacle for many therapeutic agents, TMZ is a lipophilic molecule that effectively penetrates to glioma cells. 30,36 Additionally, the blood-brain barrier surrounding these tumors is often compromised, and the highly angiogenic characteristics of glioblastoma allow TMZ concentrations in malignant areas to reach higher levels than in normal surrounding tissues.…”

Mecanismos de reparo de DNA envolvidos com lesões induzidas por agente alquilante (Nimustina) em células humanas e sua associação com a resistência de gliomas.

“…MTIC, acredita-se, é o responsável pelo efeito tóxico da droga, pela formação do íon metildiazonium, que leva à formação de O6-meG no DNA (um metabólito inativo também é formado) (Figura 9). TMZ é um composto lipofílico, capaz de atravessar a BBB e que pode ser administrado via oral (PATEL et al, 2003;REYDERMAN et al, 2004;NAGASAWA et al, 2012). Este mau pareamento é reconhecido por MMR.…”

“…MTIC, acredita-se, é o responsável pelo efeito tóxico da droga, pela formação do íon metildiazonium, que leva à formação de O6-meG no DNA (um metabólito inativo também é formado) (Figura 9). TMZ é um composto lipofílico, capaz de atravessar a BBB e que pode ser administrado via oral (PATEL et al, 2003;REYDERMAN et al, 2004;NAGASAWA et al, 2012). por ACNU é uma lesão instável que sofre espontaneamente um rearranjo intramolecular, formando N1-O6-etanoG e, subsequentemente, um ICL (N1-guanina-N3-citosina) (Figura 9) (GOMBAR;LUDLUM, 1980;KIRK;LUDLUM, 1981;.…”