Elimination pathways of [14C]losoxantrone in four cancer patients. |
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Authors: | A S Joshi H J Pieniaszek E E Vokes N J Vogelzang A F Davidson L E Richards M F Chai M Finizio M J Ratain |
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Institution: | Drug Metabolism and Pharmacokinetics, DuPont Pharmaceuticals Company, Newark and Wilmington, Delaware, USA. |
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Abstract: | Losoxantrone is an anthrapyrazole derivative in Phase III development in the U.S. for solid tumors, notably breast cancer. To obtain information on the routes of elimination of the drug, a study was conducted in four patients with advanced solid tumors, which involved intravenous administration of 100 microCi of 14C]losoxantrone for a total dose of 50 mg/m(2) during the first 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 from urine and feces was 70% with the majority (87%) of this radioactivity excreted in the feces, presumably via biliary excretion. Feces extracts were profiled for metabolites using a high-performance liquid chromatography method developed to separate synthetic standards of previously identified human urinary metabolites. Only intact losoxantrone was found in the feces. About 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 indicate that fecal excretion of unmetabolized drug via biliary and/or intestinal excretion is the primary pathway of intravenously administered losoxantrone elimination in cancer patients with refractory solid tumors. |
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