Absorption, metabolism, and excretion of C-14-temozolomide following oral administration to patients with advanced cancer

The purpose of this study is to characterize the absorption, metabolism and excretion of carbon 14-labeled temozolomide (C-14-TMZ) administered p.o. t o adult patients with advanced solid malignancies. On day 1 of cycle 1, six patients received a single oral 200-mg dose of C-1 4-TMZ (70.2 mu Ci). Whole blood, plasma, urine, and feces were collected fr om days 1-8 and on day 14 of cycle 1. Total radioactivity was measured in a ll samples. TMZ, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), an d 4-amino-5-imidazole-carboxamide (AIC) concentrations were determined in p lasma, and urine and plas ma samples were profiled for metabolite/degradati on products. Maximum TMZ plasma concentrations were achieved between 0.33 to 2 h (mean, 1.2 h), and half-life, apparent volume of distribution, and oral clearance values averaged 1.9 h, 17 liters/m(2), and 104 ml/min/m(2), respectively. A first-order absorption, one-compartment linear model, which included first -order formation of MTIC from TMZ and elimination of MTIC via degradation t o AIC, and a peripheral distribution compartment for AIC, adequately descri bed the plasma TMZ, MTIC, and AIC concentrations. MTIC systemic clearance w as estimated to be 5384 ml/min/m(2), and the half-life was calculated to be 2.5 min. Metabolite profiles of plasma at 1 and 4 h after treatment showed that C-14-derived radioactivity was primarily associated with TMZ, and a s maller amount was attributed to AIC, Profiles of urine samples from 0-24 h revealed that C-14-TMZ-derived urinary radioactivity was primarily associat ed with unchanged drug (5.6%), AIC (12%), or 3-methyl-2,3-dihydro-4-oxoimid azo[5,1-d]tetrazine-8-carboxylic acid (2.3%), The recovered radioactive dos e (39%) was principally eliminated in the urine (38%), and a small amount ( 0.8%) was excreted in the feces. TMZ exhibits rapid oral absorption and high systemic availability. The prim ary elimination pathway for TMZ is by pa-dependent degradation to MTIC and further degradation to AIC. Incomplete recovery of radioactivity may be exp lained by the incorporation of AIC into nucleic acids.