Tier 3 — preclinical

Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite

Touil YS, Auzeil N, Boulinguez F, Saighi H, Regazzetti A, Scherman D, Chabot GG

Biochemical Pharmacology 2011 82(11):1731-9

Bibliography

DOI: 10.1016/j.bcp.2011.07.097
PubMed: PMID 21840301
Funding: Not explicitly stated in the reviewed sections; conducted at Université Paris Descartes / INSERM U1022 / CNRS UMR8151, Chimie ParisTech, Paris.
Competing interests: Not stated in the reviewed sections.

Study snapshot

Design	Pharmacokinetic study in mice given fisetin 223 mg/kg intraperitoneally, with HPLC/HPLC-MS/MS metabolite identification in plasma and Lewis lung tumour tissue, plus in vitro comparison of fisetin versus its methoxylated metabolite geraldol on tumour cell cytotoxicity and endothelial cell migration/proliferation.
Model	Female C57BL/6J mice (pharmacokinetics) and Lewis lung carcinoma (LLC)-bearing mice (tumour tissue metabolite levels); LLC, NIH 3T3 and EAhy926 endothelial cell lines in vitro.
Sample	n=3 mice per sampling time point (pharmacokinetic arm); in vitro assays performed in quadruplicate, repeated 3 times.
Intervention	Single intraperitoneal dose of fisetin, 223 mg/kg, versus in vitro dosing of fisetin or geraldol (0 to 1 mM) on cell lines.
Duration	Plasma sampled over 24 hours post-dose; in vitro cytotoxicity assessed at 24-48 hours.
Endpoints	Plasma fisetin concentration-time profile (Cmax, half-life, AUC); Identification and quantification of fisetin metabolites (glucuronides, geraldol) by HPLC-MS/MS; Fisetin and geraldol concentration in Lewis lung tumour tissue; In vitro cytotoxicity (MTT assay) of fisetin vs. geraldol; Endothelial cell migration and proliferation (antiangiogenic activity)

What the study showed, in plain terms

Fisetin's anticancer activity in mice was well documented by 2011, but nobody had characterised what actually happens to it in the body — how fast it's cleared, and what it turns into.

This French team gave mice a single anticancer-effective dose of fisetin and tracked it and its breakdown products in blood and in Lewis lung tumours, then tested the main new metabolite they found, called geraldol, side-by-side with fisetin itself.

Fisetin was cleared from plasma very quickly (terminal half-life about 3.1 hours) and extensively converted to glucuronide conjugates, but one previously uncharacterised metabolite — geraldol, a methoxylated form of fisetin — reached higher concentrations than fisetin itself inside the tumours, and turned out to be more cytotoxic to cancer cells and better at blocking endothelial cell migration than the parent compound.

Bottom line: this reframes fisetin's anticancer activity in mice as partly mediated by an active metabolite rather than fisetin alone — relevant to interpreting any oral fisetin pharmacokinetics or dosing claims, though this is a single-dose mouse study.

Key findings

After a single 223 mg/kg intraperitoneal dose in mice, fisetin was rapidly cleared from plasma (terminal half-life ~3.1 h) and extensively glucuronidated; a previously unidentified methoxylated metabolite, geraldol (3,4',7-trihydroxy-3'-methoxyflavone), reached higher concentrations than fisetin in Lewis lung tumour tissue and was more cytotoxic to tumour cells and more effective at inhibiting endothelial cell migration/proliferation than fisetin itself.

What this study can and cannot tell us

Single intraperitoneal dose and mouse-only pharmacokinetics; not directly applicable to oral human dosing. Small sampling size (n=3 per time point). Geraldol's in vivo activity was inferred from tissue concentration and separate in vitro potency testing, not from direct in vivo efficacy comparison against fisetin.