In vitroandin vivophase II metabolism of combretastatin A-4: Evidence for the formation of a sulphate conjugate metabolite
- 1 February 2009
- journal article
- research article
- Published by Informa UK Limited in Xenobiotica
- Vol. 39 (2), 148-161
- https://doi.org/10.1080/00498250802566976
Abstract
Combretastatin A-4 (CA-4), is a natural compound with a potent tubulin polymerization and cell growth inhibitor properties. For these reasons CA-4 is one of the most potent anti-vascular agents that shows strong cytotoxicity against a variety of human cancer cells, including multi-drug-resistant cancer cell lines. In order to complete the knowledge of metabolic fate of CA-4, the in vitro and in vivo phase II metabolism was investigated. Both in incubation with rat and human liver S9 preparation in the presence of 39-phosphoadenosine-5´-phosphosulfate (PAPS) as a cofactor the formation of a previously no reported sulphate metabolite was demonstrated through liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) data and comparison with a synthetic reference sample. In incubation of CA-4 using rat and human liver microsomes, the formation of CA-4 glucuronide was observed and chromatographic and mass spectral properties of the metabolite were achieved and compared with those of a synthetic reference sample. Incubation of CA-4 with rat and human liver S9 preparation in the presence of uridine-5´-diphosphoglucuronic acid trisodium salt (UDPGA) and an β-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)-regenerating system as cofactors resulted in the formation of glucuronides arising from phase I CA-4 metabolites. When CA-4 was administered intraperitoneally to rat at a dose of 30 mg kg−1, both glucuronide and sulphate metabolites were observed in LC-ESI-MS-MS chromatograms and their mass spectral data were identical to those obtained from synthetic standards.Keywords
This publication has 13 references indexed in Scilit:
- In Vitro Metabolism Study of Combretastatin A-4 in Rat and Human Liver MicrosomesDrug Metabolism and Disposition, 2007
- Pharmaceutical Design of Antimitotic Agents Based on CombretastatinsCurrent Pharmaceutical Design, 2005
- Resveratrol glucuronides as the metabolites of resveratrol in humans: Characterization, synthesis, and anti-HIV activityJournal of Pharmaceutical Sciences, 2004
- Identification of 2,3-diaminophenazine and ofo-benzoquinone dioxime as the majorin vitrometabolites of benzofuroxanXenobiotica, 2004
- Comparative Preclinical Pharmacokinetic and Metabolic Studies of the Combretastatin Prodrugs Combretastatin A4 Phosphate and A1 PhosphateClinical Cancer Research, 2004
- Phase I Clinical Trial of Weekly Combretastatin A4 Phosphate: Clinical and Pharmacokinetic ResultsJournal of Clinical Oncology, 2003
- Biosynthesis of drug glucuronides for use as authentic standardsJournal of Pharmacological and Toxicological Methods, 2002
- Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liverXenobiotica, 2000
- Synthesis of water-soluble sugar derivatives of combretastatin A-4Journal of the Chemical Society, Perkin Transactions 1, 1995
- Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4Cellular and Molecular Life Sciences, 1989