Bile Is a Selective Elevator for Mucosal Mechanics and Transport

Area of Science:

• Gastroenterology
• Biophysics
• Pharmacology

Background:

• Intestinal mucus provides mechanical protection and influences drug absorption.
• The specific role of bile in mucus biomechanics and drug transport remains largely uncharacterized.

Purpose of the Study:

• To investigate the impact of bile on intestinal mucosal biomechanics.
• To determine how bile affects drug transport within the mucus layer.
• To correlate drug-bile interactions with drug-mucin interactions and in vivo bioavailability.

Main Methods:

• Utilized Brillouin imaging to assess mucus stiffening dynamics.
• Employed differential dynamic microscopy to analyze drug diffusion kinetics in mucus.
• Conducted in vivo rat studies with bile acid sequestrants.
• Clustered over 50 drugs based on bile and mucin interaction profiles.

Main Results:

• Bile exhibited square-root-of-time diffusion kinetics and caused transient mucus stiffening.
• Mucus diffusion transitioned from subdiffusive to Brownian-like in the presence of bile.
• Bile-interacting drugs (Fluphenazine, Perphenazine) diffused faster in mucus with bile.
• Non-bile-interacting drug (Metoprolol) diffusion remained consistent.
• Rat studies showed reduced Perphenazine bioavailability with bile acid sequestrants, but not Metoprolol.
• Drug-bile interaction correlated with drug-mucin interaction, but not vice versa.

Conclusions:

• Bile significantly influences intestinal mucus biomechanics and drug diffusion properties.
• A drug's ability to interact with bile is a predictor of its interaction with mucus.
• Understanding bile-mucus-drug interactions is crucial for predicting and optimizing oral drug absorption.