title: Metabolism and elimination of 5,6-dimethylxanthenone-4-acetic acid in the isolated perfused rat liver.
abstract: 5,6-Dimethylxanthenone-4-acetic acid (DXAA) is a synthetic xanthenone derivative that is active against murine solid tumors and is being formulated for clinical trials. This study used the isolated perfused rat liver to compare the hepatic metabolism and biliary excretion of DXAA with flavone-8-acetic acid (FAA), a synthetic flavonoid undergoing clinical evaluation as an anticancer drug. Perfusate, bile, and liver samples were assayed for parent drug and metabolites by HPLC. Three FAA metabolites were present in bile, and one of these coeluted with FAA acyl glucuronide. Alkaline hydrolysis of high-dose DXAA bile samples resulted in the disappearance of 5 of 7 metabolite peaks. One biliary metabolite was identified by mass spectrometry as the acyl glucuronide and its presence in bile accounted for > 50% of the DXAA dose. A second compound that was resistant to alkaline hydrolysis was characterized as a hydroxylated DXAA metabolite. A total of 28% of the high dose DXAA was recovered unchanged in the perfusate, liver, and bile, compared with 11% of the low dose DXAA and 40% of the FAA dose. Protein binding of DXAA in perfusate was saturable, ranging from 94.5% at 112 microM to 72.4% at 1125 microM, whereas binding in human plasma was > 99% at concentrations between 11.5 and 1243 microM. This study demonstrates that DXAA undergoes extensive acyl glucuronidation followed by biliary excretion in the isolated perfused rat liver. Its hepatic metabolism may be saturable, and DXAA seems to be more extensively metabolized than FAA. Finally, DXAA protein binding in human plasma is high and not dose-dependent at concentrations likely to be clinically relevant.
authors.affiliation: Research Division, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
authors.forename: L K
authors.initials: LK
authors.lastname: Webster
authors.forename: A G
authors.initials: AG
authors.lastname: Ellis
authors.forename: P
authors.initials: P
authors.lastname: Kestell
authors.forename: G W
authors.initials: GW
authors.lastname: Rewcastle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism*; D005965:Glucuronates / Q000737:chemistry*; D020723:Glucuronic Acid; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014966:Xanthenes / Q000378:metabolism*; D044004:Xanthones
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D005965:Glucuronates; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; C049328:flavone acetic acid; D020723:Glucuronic Acid