Elimination pathways of [C-14]losoxantrone in four cancer patients

Losoxantrone is an anthrapyrazole derivative in Phase III development in th e U.S. for solid tumors, notably breast cancer. To obtain information on th e routes of elimination of the drug, a study was conducted in four patients with advanced solid tumors, which involved intravenous administration of 1 00 mu Ci of [C-14]losoxantrone for a total dose of 50 mg/m(2) during the fi rst course of losoxantrone therapy. Blood, urine, and feces were collected for up to 2 weeks and were analyzed for total radioactivity and parent drug . In addition, feces were profiled for the presence of metabolites. Plasma concentrations of total radioactivity exhibited a temporal pattern similar to the parent drug. Combined recovery of administered total radioactivity f rom urine and feces was 70% with the majority (87%) of this radioactivity e xcreted in the feces, presumably via biliary excretion. Feces extracts were profiled for metabolites using a high-performance liquid chromatography me thod developed to separate synthetic standards of previously identified hum an urinary metabolites. Only intact losoxantrone was found in the feces. Ab out 9% of the dose was excreted in the urine, primarily during the first 24 h and mostly in the form of parent compound. Collectively, these data indi cate that fecal excretion of unmetabolized drug via biliary and/or intestin al excretion is the primary pathway of intravenously administered losoxantr one elimination in cancer patients with refractory solid tumors.