PHARMACOKINETICS OF 3-METHYL-(TRIAZEN-1-YL)IMIDAZOLE-4-CARBOXIMIDE FOLLOWING ADMINISTRATION OF TEMOZOLOMIDE TO PATIENTS WITH ADVANCED CANCER

The antitumor activity of temozolomide (TMZ) is believed to arise via formation of the reactive, alkylating metabolite 3-methyl-(triazen-1-y l)imidazole-4-carboximide (MTIC), which is produced by chemical hydrol ysis of the parent drug, MTIC has not been quantitated in plasma or ur ine following administration of TMZ to patients, We developed a sensit ive, specific method for the determination of MTIC levels in plasma, b ased on reverse-phase high-pressure liquid chromatography of the super natant 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 prot eins with methanol, and storage of the methanolic supernatant at -70 d egrees C, The pharmacokinetics of MTIC were studied in 15 patients who received 125-250 mg/m(2) TMZ, Peak plasma concentrations of 0.07-0.61 mu g/ml MTIC were observed approximately 1 h after a p.o. dose of TMZ , Appearance and disappearance (t(1/2), 88 min) of the reactive metabo lite 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 th e values for TMZ, MTIC did not accumulate in plasma following five con secutive daily doses of TMZ.