TY - JOUR
T1 - Pharmacokinetics of 3-methyl-(triazen-1-yl)imidazole-4-carboximide following administration of temozolomide to patients with advanced cancer
AU - Reid, Joel M.
AU - Stevens, David C.
AU - Rubin, Joseph
AU - Ames, Matthew M.
PY - 1997/12
Y1 - 1997/12
N2 - The antitumor activity of temozolomide (TMZ) is believed to arise via formation of the reactive, alkylating metabolite 3-methyl-(triazen-1- yl)imidazole-4-carboximide (MTIC), which is produced by chemical hydrolysis of the parent drug. MTIC has not been quantitated in plasma or urine following administration of TMZ to patients. We developed a sensitive, specific method for the determination of MTIC levels in plasma, based on reverse-phase high-pressure liquid chromatography of the supernatant that is obtained by methanol precipitation of plasma proteins. Due to poor stability under physiological conditions, determination of MTIC required rapid specimen processing, precipitation of plasma proteins with methanol, and storage of the methanolic supernatant at -70°C. The pharmacokinetics of MTIC were studied in 15 patients who received 125-250 mg/m2 TMZ. Peak plasma concentrations of 0.07-0.61 μg/ml MTIC were observed approximately 1 h after a p.o. dose of TMZ. Appearance and disappearance (t( 1/4 ), 88 min) of the reactive metabolite paralleled the appearance and disappearance of TMZ in plasma. The mean values of the metabolite peak plasma concentration and AUC were 2.6% (range, 1.6-4.6%) and 2.2% (range, 0.8-3.6%), respectively, of the values for TMZ. MTIC did not accumulate in plasma following five consecutive daily doses of TMZ.
AB - The antitumor activity of temozolomide (TMZ) is believed to arise via formation of the reactive, alkylating metabolite 3-methyl-(triazen-1- yl)imidazole-4-carboximide (MTIC), which is produced by chemical hydrolysis of the parent drug. MTIC has not been quantitated in plasma or urine following administration of TMZ to patients. We developed a sensitive, specific method for the determination of MTIC levels in plasma, based on reverse-phase high-pressure liquid chromatography of the supernatant that is obtained by methanol precipitation of plasma proteins. Due to poor stability under physiological conditions, determination of MTIC required rapid specimen processing, precipitation of plasma proteins with methanol, and storage of the methanolic supernatant at -70°C. The pharmacokinetics of MTIC were studied in 15 patients who received 125-250 mg/m2 TMZ. Peak plasma concentrations of 0.07-0.61 μg/ml MTIC were observed approximately 1 h after a p.o. dose of TMZ. Appearance and disappearance (t( 1/4 ), 88 min) of the reactive metabolite paralleled the appearance and disappearance of TMZ in plasma. The mean values of the metabolite peak plasma concentration and AUC were 2.6% (range, 1.6-4.6%) and 2.2% (range, 0.8-3.6%), respectively, of the values for TMZ. MTIC did not accumulate in plasma following five consecutive daily doses of TMZ.
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M3 - Article
C2 - 9815639
AN - SCOPUS:0031426782
SN - 1078-0432
VL - 3
SP - 2393
EP - 2398
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 12 I
ER -