Tier 4 — mechanistic

Selective inhibition of CYP2C8 by fisetin and its methylated metabolite, geraldol, in human liver microsomes

Riya Shrestha, Ju-Hyun Kim, Wongshik Nam, Hye Suk Lee, Jae-Mok Lee, Sangkyu Lee
Drug Metabolism and Pharmacokinetics 2018 33(2):111–117

Bibliography

PubMed
PMID 29454704
DOI
10.1016/j.dmpk.2017.12.006

Study snapshot

DesignIn-vitro CYP enzyme assay using pooled human liver microsomes with LC-MS/MS; inhibition mode characterized by kinetic plots.
ModelPooled human liver microsomes; no trial participants.
SampleIn-vitro pooled liver microsome experiments; not a participant-based clinical study.
InterventionFisetin and its methoxylated metabolite geraldol tested at experimental concentrations against CYP activity, with paclitaxel hydroxylation used for CYP2C8 confirmation.
DurationIn-vitro kinetic and microsomal enzyme assays; no clinical dosing period or participant follow-up.
EndpointsCYP2C8-catalyzed paclitaxel hydroxylation; Reversible versus mechanism-based inhibition; Noncompetitive inhibition kinetic constants

What the study showed, in plain terms

In pooled human liver microsomes fisetin and its metabolite geraldol inhibited CYP2C8 activity in a reversible, noncompetitive manner. The reported inhibitory constants were 4.1 µM for fisetin and 11.5 µM for geraldol. This is laboratory mechanistic evidence: the study did not administer fisetin with paclitaxel or another medicine to humans, and no clinical interaction magnitude or frequency can be inferred.

Key findings

Human liver microsome experiment, not a human trial. CYP2C8-mediated paclitaxel hydroxylation was selectively inhibited by fisetin and geraldol.

Reversible, noncompetitive inhibition: Ki 4.1 µM for fisetin; Ki 11.5 µM for geraldol.

Concentration- and formulation-specific human in-vivo drug interactions remain unquantified.

What this study can and cannot tell us

Only pooled microsomes, with no human coadministration, tissue distribution, repeated dosing or clinical outcome assessment.

Micromolar experimental concentrations do not directly translate to free hepatic exposure after standard oral supplements.

The experiment supports medication-review caution, not a quantified contraindication.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology