A Novel In Vitro Membrane Permeability Methodology Using Three-dimensional Caco-2 Tubules in a Microphysiological System Which Better Mimics In Vivo Physiological Conditions

• Published in: Journal of pharmaceutical sciences Vol. 111; no. 1; p. 214
• Main Authors: Hagiwara, Yuki, Kumagai, Harumi, Ouwerkerk, Niels, Gijzen, Linda, Annida, Rumaisha, Bokkers, Marleen, van Vught, Remko, Yoshinari, Kouichi, Katakawa, Yoshifumi, Motonaga, Kei, Tajiri, Tomokazu
• Format: Journal Article
• Language: English
• Published: United States 01-01-2022
• Subjects: Bile Acids and Salts; Caco-2 Cells; Cell Membrane Permeability; Gastrointestinal Tract; Humans; Intestinal Absorption; Permeability; bile acids; organ-on-a-chip/microphysiological system (MPS); permeability; three-dimensional culture Caco-2 monolayer
• ISSN: 1520-6017
• DOI: 10.1016/j.xphs.2021.11.016

The aim of this study was to develop an in vitro drug permeability methodology which mimics the gastrointestinal environment more accurately than conventional 2D methodologies through a three-dimensional (3D) Caco-2 tubules using a microphysiological system. Such a system offers significant advantages, including accelerated cellular polarization and more accurate mimicry of the in vivo environment. This methodology was confirmed by measuring the permeability of propranolol as a model compound, and subsequently applied to those of solifenacin and bile acids for a comprehensive understanding of permeability for the drug product in the human gastrointestinal tract. To protect the Caco-2 tubules from bile acid toxicity, a mucus layer was applied on the surface of Caco-2 tubules and it enables to use simulated intestinal fluid. The assessment using propranolol reproduced results equivalent to those obtained from conventional methodology, while that using solifenacin indicated fluctuations in the permeability of solifenacin due to various factors, including interaction with bile acids. We therefore suggest that this model will serve as an alternative testing system for measuring drug absorption in an environment closely resembling that of the human gastrointestinal tract.