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Fraxetin Inhibits UGT1A1 and UGT1A9 Activities In Vitro: Inhibition Kinetics, Molecular Dynamics Simulation, and
Jinqian Chen1, Han Han2, Jibin Li1
1NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China.
Pharmaceuticals (Basel, Switzerland)
|June 26, 2026
Summary
Fraxetin, a traditional Chinese medicine component, moderately inhibits UGT1A1 and UGT1A9 enzymes. This suggests a potential herb-drug interaction risk, particularly in the gut, warranting further clinical investigation.
Area of Science:
- Pharmacology and Toxicology
- Drug Metabolism and Pharmacokinetics
- Herbal Medicine Interactions
Background:
- Fraxetin, derived from Cortex Fraxini, is a coumarin used in traditional Chinese medicine.
- While known to be metabolized by UGT1A9, its potential to inhibit UDP-glucuronosyltransferase (UGT) enzymes and cause herb-drug interactions (HDIs) remains largely unstudied.
Purpose of the Study:
- To investigate the inhibitory potential of fraxetin on human UGT enzymes.
- To characterize the kinetics and molecular interactions of fraxetin with UGT isoforms.
- To assess the risk of herb-drug interactions using in vitro-in vivo extrapolation (IVIVE).
Main Methods:
- Screening of fraxetin and related coumarins against 11 recombinant human UGTs.
- Kinetic analysis, molecular docking, molecular dynamics simulations, and MM/GBSA/PBSA calculations.
- FDA 2020 IVIVE methodology to predict interaction risk.
Main Results:
- Fraxetin demonstrated significant inhibition of UGT1A1 and UGT1A9, acting as a mixed-type inhibitor.
- Molecular modeling suggested a specific binding interaction favoring UGT1A9.
- IVIVE predicted a high risk of herb-drug interaction within the intestinal lumen, exceeding the threshold for systemic risk.
Conclusions:
- Fraxetin is identified as a moderate-potency inhibitor of UGT1A1 and UGT1A9.
- A previously unrecognized herb-drug interaction risk associated with fraxetin is highlighted, primarily localized to the gut.
- Clinical confirmation is recommended to validate this potential interaction signal.
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