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Bile Is a Selective Elevator for Mucosal Mechanics and Transport
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    Bile Is a Selective Elevator for Mucosal Mechanics and Transport
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    • Simon Hanio
      Simon Hanio
      Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
      More by Simon Hanio
    • Stephanie Möllmert
      Stephanie Möllmert
      Max Planck Institute for the Science of Light and Max-Planck-Zentrum für Physik und Medizin, Staudtstrasse 2, 91058 Erlangen, Germany
    • Conrad Möckel
      Conrad Möckel
      Max Planck Institute for the Science of Light and Max-Planck-Zentrum für Physik und Medizin, Staudtstrasse 2, 91058 Erlangen, Germany
    • Susobhan Choudhury
      Susobhan Choudhury
      Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany
    • Andreas I. Höpfel
      Andreas I. Höpfel
      Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany
    • Theresa Zorn
      Theresa Zorn
      Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Wuerzburg, Germany
      More by Theresa Zorn
    • Sebastian Endres
      Sebastian Endres
      Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Wuerzburg, Germany
    • Jonas Schlauersbach
      Jonas Schlauersbach
      Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
    • Lena Scheller
      Lena Scheller
      Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
    • Christoph Keßler
      Christoph Keßler
      Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
    • Oliver Scherf-Clavel
      Oliver Scherf-Clavel
      Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
    • Peter Bellstedt
      Peter Bellstedt
      Institute of Organic Chemistry, University of Jena, Humboldtstrasse 10, 07743 Jena, Germany
      Institute for Clinical Chemistry, University of Zürich,Rämistrasse 100, 8091 Zurich, Switzerland
    • Ulrich S. Schubert
      Ulrich S. Schubert
      Institute of Organic Chemistry, University of Jena, Humboldtstrasse 10, 07743 Jena, Germany
      Jena Center for Soft Matter (JCSM), University of Jena, Philosophenweg 7, 07743 Jena, Germany
    • Ann-Christin Pöppler
      Ann-Christin Pöppler
      Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Wuerzburg, Germany
    • Katrin G. Heinze
      Katrin G. Heinze
      Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany
    • Jochen Guck*
      Jochen Guck
      Max Planck Institute for the Science of Light and Max-Planck-Zentrum für Physik und Medizin, Staudtstrasse 2, 91058 Erlangen, Germany
      *Email: [email protected]
      More by Jochen Guck
    • Lorenz Meinel*
      Lorenz Meinel
      Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
      Helmholtz Institute for RNA-based Infection Research (HIRI), Josef-Schneider-Strasse 2, 97080 Wuerzburg, Germany
      *Email: [email protected]
    Other Access OptionsSupporting Information (2)

    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2023, 20, 12, 6151–6161
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.molpharmaceut.3c00550
    Published October 31, 2023
    Copyright © 2023 The Authors. Published by American Chemical Society

    Abstract

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    Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on mucosal biomechanics and drug transport within mucus. Bile diffused with square-root-of-time kinetics and interplayed with mucus, leading to transient stiffening captured in Brillouin images and a concentration-dependent change from subdiffusive to Brownian-like diffusion kinetics within the mucus demonstrated by differential dynamic microscopy. Bile-interacting drugs, Fluphenazine and Perphenazine, diffused faster through mucus in the presence of bile, while Metoprolol, a drug with no bile interaction, displayed consistent diffusion. Our findings were corroborated by rat studies, where co-dosing of a bile acid sequestrant substantially reduced the bioavailability of Perphenazine but not Metoprolol. We clustered over 50 drugs based on their interactions with bile and mucin. Drugs that interacted with bile also interacted with mucin but not vice versa. This study detailed the dynamics of mucus biomechanics under bile exposure and linked the ability of a drug to interact with bile to its abbility to interact with mucus.

    Copyright © 2023 The Authors. Published by American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.3c00550.

    • Additional experimental results, details, materials, and methods; Fluorescence correlation spectroscopy, fluorescein isothiocyanate-dextran release, rheology, nuclear magnetic resonance spectroscopy, Brillouin microscopy, differential dynamic microscopy, flux, high-pressure liquid chromatography, liquid chromatography-tandem mass spectrometry, pharmacokinetic studies in rats, and dynamic light scattering (Figures S1–S48), (Tables S1–S7) (PDF)

    • Theoretical calculations using diffusion reaction networks (MP4)

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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2023, 20, 12, 6151–6161
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.molpharmaceut.3c00550
    Published October 31, 2023
    Copyright © 2023 The Authors. Published by American Chemical Society

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