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Development of a Multicellular Three-dimensional Organotypic Model of the Human Intestinal Mucosa Grown Under Microgravity
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Human Primary Cell-Based Organotypic Microtissues for Modeling Small Intestinal Drug Absorption
Seyoum Ayehunie1, Tim Landry2, Zachary Stevens2
1MatTek Corporation, 200 Homer Avenue, Ashland, Massachusetts, USA. sayehunie@mattek.com.
Pharmaceutical Research
|February 25, 2018
Summary
New small intestinal (SMI) microtissues accurately predict oral drug bioavailability and drug interactions. These 3D models offer a superior alternative to Caco-2 cells for preclinical drug absorption assessment.
Area of Science:
- Pharmacology
- Drug Discovery
- In Vitro Models
Background:
- Predicting oral drug absorption and interactions is crucial for preclinical drug development.
- Current in vitro models like Caco-2 cells have limitations in accurately reflecting human intestinal physiology.
- Novel organotypic microtissues offer a promising alternative for improved prediction.
Purpose of the Study:
- To evaluate novel, primary human cell-based organotypic small intestinal (SMI) microtissues.
- To assess their utility in predicting intestinal drug absorption.
- To determine their capability in modeling drug-drug interactions.
Main Methods:
- SMI microtissues were constructed using human intestinal fibroblasts and enterocytes on a permeable support.
- Drug permeability was assessed using 11 benchmark drugs with known human absorption data.
- Drug-drug interactions were investigated using transporter substrates and inhibitors.
Main Results:
- SMI microtissues mimicked the structural and barrier properties of the human small intestine.
- They expressed key drug transporters and metabolizing enzymes.
- Microtissues showed better correlation with human absorption data (r²=0.91) than Caco-2 cells (r²=0.71) and confirmed transporter functionality.
Conclusions:
- Small intestinal (SMI) microtissues are a valuable preclinical tool.
- They can accurately predict the bioavailability of orally administered drugs.
- This model enhances the prediction of drug absorption and interactions.
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