title: Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite.
abstract: Although the natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) has been recently identified as an anticancer agent with antiangiogenic properties in mice, its in vivo pharmacokinetics and metabolism are presently not characterized. Our purpose was to determine the pharmacokinetics and metabolism of fisetin in mice and determine the biological activity of a detected fisetin metabolite. After fisetin administration of an efficacious dose of 223 mg/kg i.p. in mice, the maximum fisetin concentration reached 2.5 μg/ml at 15 min and the plasma concentration declined biphasically with a rapid half-life of 0.09 h and a terminal half-life of 3.1h. Three metabolites were detected, one of which was a glucuronide of fisetin (M1), whereas another glucuronide (M2) was a glucuronide of a previously unknown fisetin metabolite (M3). HPLC-MS/MS analysis indicated that M3 was a methoxylated metabolite of fisetin (MW=300 Da). The UV spectrum of M3 was identical to that of fisetin and standard 3,4',7-trihydroxy-3'-methoxyflavone (geraldol). In addition, because M3 co-eluted with standard geraldol in 4 different chromatographic ternary gradient conditions, M3 was therefore assigned to geraldol. Of interest, this metabolite was shown to achieve higher concentrations than fisetin in Lewis lung tumors. We also compared the cytotoxic and antiangiogenic activities of fisetin and geraldol in vitro and it was found that the latter was more cytotoxic than the parent compound toward tumor cells, and that it could also inhibit endothelial cells migration and proliferation. In conclusion, these results suggest that fisetin metabolism plays an important role in its in vivo anticancer activities.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Institut National de Santé et de Recherche Médicale (Inserm U1022), Centre National de Recherche Scientifique (CNRS UMR8151), Chimie ParisTech, Laboratoire de pharmacologie chimique, génétique & imagerie, Paris F-75006, France.
authors.forename: Yasmine S
authors.initials: YS
authors.lastname: Touil
authors.forename: Nicolas
authors.initials: N
authors.lastname: Auzeil
authors.forename: François
authors.initials: F
authors.lastname: Boulinguez
authors.forename: Hanane
authors.initials: H
authors.lastname: Saighi
authors.forename: Anne
authors.initials: A
authors.lastname: Regazzetti
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherman
authors.forename: Guy G
authors.initials: GG
authors.lastname: Chabot
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D047309:Flavones / Q000097:blood* / Q000494:pharmacology; D005419:Flavonoids / Q000493:pharmacokinetics* / Q000494:pharmacology; D044948:Flavonols; D020719:Glucuronides / Q000097:blood*; D007797:Laminin; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011509:Proteoglycans
chemical_list: C560847:3,4',7-trihydroxy-3'-methoxyflavone; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004338:Drug Combinations; D047309:Flavones; D005419:Flavonoids; D044948:Flavonols; D020719:Glucuronides; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; C017875:fisetin