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Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite
- Source :
- Biochemical Pharmacology, Biochemical Pharmacology, 2011, 82 (11), pp.1731-9. ⟨10.1016/j.bcp.2011.07.097⟩
- Publication Year :
- 2011
- Publisher :
- HAL CCSD, 2011.
-
Abstract
- International audience; 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.
- Subjects :
- MESH: Cell Line, Tumor
fisetin
[SDV.CAN]Life Sciences [q-bio]/Cancer
[SDV.CAN] Life Sciences [q-bio]/Cancer
MESH: Glucuronides
MESH: Mice, Inbred C57BL
MESH: Collagen
MESH: Animals
MESH: Endothelial Cells
geraldol
MESH: Mice
MESH: Cell Movement
MESH: Angiogenesis Inhibitors
MESH: Drug Combinations
MESH: Carcinoma, Lewis Lung
MESH: Flavones
MESH: Laminin
MESH: Cell Survival
MESH: Proteoglycans
Flavonoid
cytotoxicity
MESH: Antineoplastic Agents
pharmacokinetics
metabolism
MESH: Female
MESH: Flavonoids
MESH: Neoplasm Transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 00062952 and 18732968
- Database :
- OpenAIRE
- Journal :
- Biochemical Pharmacology, Biochemical Pharmacology, 2011, 82 (11), pp.1731-9. ⟨10.1016/j.bcp.2011.07.097⟩
- Accession number :
- edsair.od......1398..8728d40b4f22e60b891a2ea41ba5099b