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Green Tea Catechins Decrease Solubility of Raloxifene In Vitro and Its Systemic Exposure in Mice

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Abstract

Purpose

Green tea is a widely consumed beverage. A recent clinical study reported green tea decreased systemic exposure of raloxifene and its glucuronide metabolites by 34–43%. However, the underlying mechanism(s) remains unknown. This study investigated a change in raloxifene’s solubility as the responsible mechanism.

Methods

The effects of green tea extract, (–)-epigallocatechin gallate (EGCG), and (–)-epigallocatechin (EGC) on raloxifene’s solubility were assessed in fasted state simulated intestinal fluids (FaSSIF) and fed state simulated intestinal fluids (FeSSIF). EGCG and EGC represent green tea’s main bioactive constituents, flavan-3-gallate and flavan-3-ol catechins respectively, and the tested concentrations (mM) match the µg/mg of each compound in the extract. Our mouse study (n = 5/time point) evaluated the effect of green tea extract and EGCG on the systemic exposure of raloxifene.

Results

EGCG (1 mM) and EGC (1.27 mM) decreased raloxifene’s solubility in FaSSIF by 78% and 13%, respectively. Micelle size in FaSSIF increased with increasing EGCG concentrations (> 1000% at 1 mM), whereas EGC (1.27 mM) did not change micelle size. We observed 3.4-fold higher raloxifene solubility in FeSSIF compared to FaSSIF, and neither green tea extract nor EGCG significantly affected raloxifene solubility or micelle size in FeSSIF. The mice study showed that green tea extract significantly decreased raloxifene Cmax by 44%, whereas EGCG had no effect. Green tea extract and EGCG did not affect the AUC0-24 h of raloxifene or the metabolite-to-parent AUC ratio.

Conclusions

This study demonstrated flavan-3-gallate catechins may decrease solubility of poorly water-soluble drugs such as raloxifene, particularly in the fasted state.

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Data availability

All data supporting the findings of this study are included within the paper.

Abbreviations

AUC:

Area under the plasma concentration versus time curve

BDDCS:

Biopharmaceutics drug disposition classification system

Cg:

( +)-Catechin gallate

Cmax :

Maximum plasma concentration

EGC:

(–)-Epigallocatechin

EGCG:

(–) -Epigallocatechin gallate

FaSSIF:

Fasted state simulated intestinal fluid

FeSSIF:

Fed state simulated intestinal fluid

Gcg:

(–)-Gallocatechin gallate

tmax :

Time to Cmax

UHPLC:

Ultra-high performance liquid chromatography

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Funding

This work was supported by the National Institutes of Health National Center for Complementary and Integrative Health grants R21 AT011101 and U54 AT008909.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, 412 E. Spokane Falls Blvd, Spokane, WA, 99202, USA

    Victoria O. Oyanna, Baron J. Bechtold, Katherine D. Lynch, M. Ridge Call & John D. Clarke

  2. Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA

    Tyler N. Graf & Nicholas H. Oberlies

  3. Center of Excellence for Natural Product Drug Interaction Research, Spokane, WA, USA

    John D. Clarke

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  1. Victoria O. Oyanna
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  2. Baron J. Bechtold
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  3. Katherine D. Lynch
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  5. Tyler N. Graf
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  6. Nicholas H. Oberlies
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  7. John D. Clarke
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Contributions

Participated in research design: Victoria Oyanna and John Clarke

Conducted experiments: Victoria Oyanna, Baron Bechtold, Katherine Lynch, M. Ridge Call, and John Clarke

Contributed new reagents or analytic tools: Tyler Graf and Nicholas Oberlies

Performed data analysis: Victoria Oyanna and John Clarke

Wrote or contributed to the writing of the manuscript: Victoria Oyanna and John Clarke

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Correspondence to John D. Clarke.

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Oyanna, V.O., Bechtold, B.J., Lynch, K.D. et al. Green Tea Catechins Decrease Solubility of Raloxifene In Vitro and Its Systemic Exposure in Mice. Pharm Res 41, 557–566 (2024). https://doi.org/10.1007/s11095-024-03662-w

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