Disposition of the novel antitumour agent xanthenone-4-acetic acid in the mouse: Identification of metabolites and routes of elimination

Abstract

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 μmol/kg). Urine, plasma and bile were collected and subjected to analysis by hplc. Urine samples demonstrated labile metabolites which released XAA following incubation with β-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 α-oxidation of the acetic acid side chain and aromatic hydroxylation of the xanthenone ring.