A primary human Gut/Liver microphysiological system to estimate human oral bioavailability

Area of Science:

• Pharmacokinetics and Drug Metabolism
• In Vitro Modeling and Drug Development

Background:

• Oral bioavailability is critical for therapeutic drug efficacy, influenced by gut absorption and first-pass metabolism.
• Existing in vitro models lack the ability to fully profile the gut and liver contributions to oral bioavailability.
• Microphysiological systems (MPSs) offer a promising approach to model complex organ interactions.

Purpose of the Study:

• To develop and validate a primary human Gut/Liver microphysiological system (MPS) for pharmacokinetic (PK) investigations.
• To simulate both oral and intravenous dosing routes to assess drug absorption and metabolism.
• To mechanistically model human oral bioavailability and its contributing factors (F_a, F_g, F_h) in vitro.

Main Methods:

• Constructed an MPS comprising primary human jejunal epithelial cells and primary human hepatocytes in co-culture.
• Integrated the Gut/Liver MPS with a mechanistic mathematical model for PK parameter estimation.
• Utilized midazolam, a CYP3A substrate, to validate the system's ability to model intestinal and hepatic drug extraction.

Main Results:

• The primary Gut/Liver MPS successfully maintained the functionality of both gut and liver tissues in co-culture.
• The integrated system accurately estimated organ-specific PK parameters and human oral bioavailability.
• Demonstrated the system's capability to mechanistically model the PKs of oral compounds like midazolam.

Conclusions:

• The developed primary Gut/Liver MPS provides a novel in vitro tool to bridge the gap in profiling gut and liver contributions to bioavailability.
• This system enables more accurate prediction of oral drug performance, supporting efficient drug discovery and development.
• The MPS represents a significant advancement for understanding and optimizing oral therapeutics.