title: Elimination pathways of [14C]losoxantrone in four cancer patients.
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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, DuPont Pharmaceuticals Company, Newark and Wilmington, Delaware, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Joshi
authors.forename: H J
authors.initials: HJ
authors.lastname: Pieniaszek
authors.forename: E E
authors.initials: EE
authors.lastname: Vokes
authors.forename: N J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: A F
authors.initials: AF
authors.lastname: Davidson
authors.forename: L E
authors.initials: LE
authors.lastname: Richards
authors.forename: M F
authors.initials: MF
authors.lastname: Chai
authors.forename: M
authors.initials: M
authors.lastname: Finizio
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000880:Anthraquinones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes; D005243:Feces; D006801:Humans; D007262:Infusions, Intravenous; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D047069:Pyrazolones
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D011720:Pyrazoles; D047069:Pyrazolones; C050637:losoxantrone