Pharmacokinetics and disposition in the rat of a DNA intercalator 502U83

The pharmacokinetics, metabolism, and qualitative tissue distribution of 502U83, a compound with antineoplastic activity, were examined in the rat. After an oral dose, average maximum plasma concentrations of 5.3 micrograms/ml were achieved at 0.28 hr, indicating rapid absorption of the compound; the bioavailability was estimated to be 62%. After intravenous administration the half-life was 1.73 hr. Autoradiographs of rats dosed intravenously with [14C]502U83 showed the presence of significant levels of radioactivity in the bone marrow, salivary gland, thymus, and lung; highest levels were in the gastrointestinal tract. There was no evidence of penetration of radioactivity into the brain. After an intravenous administration of [14C]502U83, a mean of 94.1% of the dose was recovered in 72 hr, with 46.6% in the urine and 47.5% in the feces. HPLC analysis of the radiocarbon in urine and feces revealed the presence of at least six common radioactive peaks, each representing approximately 2 to 12% of the dose. Biotransformation of 502U83 by the rat mainly involves oxidation of the hydroxyethyl group, and one or both of the hydroxymethyl groups leading to three major metabolites, common to urine and feces. Parent drug was the major component in both urine and feces, respectively, accounting for 18% and 10% of the dose in 48 hr. The glucuronic acid conjugate of the parent drug was a minor metabolite (< 2% of the dose). There was no evidence of metabolism on the anthracene ring.