Geraldol

Biochemical Pharmacology, 2011, 82(11):1731-1739.

Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite.[Reference: WebLink]

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.
METHODS AND RESULTS:
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 3.1 h. 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.
CONCLUSIONS:
In conclusion, these results suggest that fisetin metabolism plays an important role in its in vivo anticancer activities.

Drug Metabolism & Pharmacokinetics,2018,33(2):111-117.

Selective inhibition of CYP2C8 by fisetin and its methylated metabolite, geraldol, in human liver microsomes.[Reference: WebLink]

Fisetin is a flavonol compound commonly found in edible vegetables and fruits. It has anti-tumor, antioxidant, and anti-inflammatory effects. Geraldol, the O-methyl metabolite of fisetin in mice, is reported to suppress endothelial cell migration and proliferation. Although the in vivo and in vitro effects of fisetin and its metabolites are frequently reported, studies on herb–drug interactions have not yet been performed. This study was designed to investigate the inhibitory effect of fisetin and Geraldol on eight isoforms of human cytochrome P450 (CYP) by using cocktail assay and LC-MS/MS analysis.
METHODS AND RESULTS:
The selective inhibition of CYP2C8-catalyzed paclitaxel hydroxylation by fisetin and Geraldol were confirmed in pooled human liver microsomes (HLMs). In addition, an IC50 shift assay under different pre-incubation conditions confirmed that fisetin and Geraldol shows a reversible concentration-dependent, but not mechanism-based, inhibition of CYP2C8. Moreover, Michaelis-Menten, Lineweaver-burk plots, Dixon and Eadie-Hofstee showed a non-competitive inhibition mode with an equilibrium dissociation constant of 4.1 μM for fisetin and 11.5 μM for Geraldol, determined from secondary plot of the Lineweaver-Burk plot.
CONCLUSIONS:
In conclusion, our results indicate that fisetin showed selective reversible and non-competitive inhibition of CYP2C8 more than its main metabolite, Geraldol, in HLMs.