Disposition of the novel antitumour agent xanthenone-4-acetic acid in the mouse: identification of metabolites and routes of elimination.
1. Xanthenone-4-acetic acid (XAA) is an experimental antitumour agent which resembles flavone-8-acetic acid in its induction of cytokine synthesis, nitric oxide production and tumour haemorrhagic necrosis. We have investigated the excretion and metabolic fate of XAA in the BDF1 mouse. 2. XAA was administered intravenously at the maximal tolerated dose (1090 mumol/kg). Urine, plasma and bile were collected and subjected to analysis by hplc. Urine samples demonstrated labile metabolites which released XAA following incubation with beta-glucuronidase/sulphatase or at pH 9.0. The structures of isolated XAA metabolites were characterized by ms or 1H-NMR spectra at 400 MHz. 3. The major metabolite pathway of XAA involves conjugation with glucuronic acid, since the resulting metabolite, XAA acyl glucuronide, accounts for 25% of the dose excreted in the urine. Other metabolite pathways include alpha-oxidation of the acetic acid side chain and aromatic hydroxylation of the xanthenone ring.
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
P
P
Kestell
G W
GW
Rewcastle
B C
BC
Baguley
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005966:Glucuronidase / Q000378:metabolism; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013429:Sulfatases / Q000378:metabolism; D014966:Xanthenes / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine
D000970:Antineoplastic Agents; D014966:Xanthenes; C066138:xanthenone-4-acetic acid; D013429:Sulfatases; D005966:Glucuronidase