An In-Depth View into Human Intestinal Fluid Colloids: Intersubject Variability in Relation to Composition

Area of Science:

• Gastroenterology
• Pharmaceutics
• Biophysical Chemistry

Background:

• Intestinal fluids influence oral drug absorption.
• Current simulated intestinal fluids (SIF) lack detailed ultrastructural characterization.
• Colloidal structures in intestinal fluids affect drug solubilization and bioavailability.

Purpose of the Study:

• To comprehensively characterize the ultrastructure of human intestinal fluids (HIF).
• To compare HIF ultrastructure with simulated intestinal fluids (SIF).
• To investigate intersubject variability in HIF ultrastructure and its relation to drug absorption.

Main Methods:

• Collected and compositionally characterized fasted and fed-state HIF from human volunteers.
• Employed cryo-transmission electron microscopy (cryo-TEM), negative stain TEM, and cryo-scanning electron microscopy (cryo-SEM).
• Compared ultrastructure of individual and pooled HIF with fasted state simulated intestinal fluids (FaSSIF) and fed state simulated intestinal fluids (FeSSIF).

Main Results:

• Fasted state HIF (FaHIF) and FaSSIF showed minimal intersubject variability, primarily consisting of (mixed)-micelles.
• Fed state simulated intestinal fluids (FeSSIF) lack crucial colloidal structures like (multi)-lamellar vesicles and lipid droplets found in fed state HIF (FeHIF).
• Significant intersubject variability in FeHIF ultrastructure was observed, potentially explaining variable lipophilic drug absorption.

Conclusions:

• Current FeSSIF are not representative of native FeHIF ultrastructure.
• Intersubject variability in FeHIF colloidal structures is a critical factor for drug absorption.
• Advanced electron microscopy techniques provide essential insights into HIF ultrastructure for improved drug formulation.