Disposition and pharmacokinetics of temozolomide in rat.
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.
Reyderman
L
L
Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033-1300, USA. larisa.reyderman@spcorp.com
Statkevich
P
P
Thonoor
C M
CM
Patrick
J
J
Batra
V K
VK
Wirth
M
M
D000284:Administration, Oral; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D000077204:Temozolomide; D014018:Tissue Distribution
D018906:Antineoplastic Agents, Alkylating; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D003606:Dacarbazine; C010243:5-(3-methyl-1-triazeno)imidazole-4-carboxamide; D000077204:Temozolomide