Advances in cell-based permeability assays to screen drugs for intestinal absorption

ABSTRACT

Introduction: Successful oral therapy requires sufficient intestinal absorption to enable the drug to reach its site of action. Evaluation of intestinal permeability is important for candidate selection during drug discovery and development. In vitro cell assays that correlate with human intestinal absorption serve as an alternative to more expensive and low-throughput preclinical or clinical in vivo methods to investigate a drug’s intestinal permeability.

Areas covered: This article focuses on cell-based models utilized to predict in vivo intestinal drug permeability. This includes the utilization of the Caco-2 and other cell epithelial lines, human primary intestinal cells, and induced pluripotent stem cells. Additional topics include co-cultures, three-dimensional models, and microfluidic systems.

Expert opinion: In vitro permeability assays are utilized to predict a drug’s permeability class or intestinal fraction absorbed. Newer Caco-2 co-cultures, intestinal epithelial cells, and three-dimensional models better replicate the architecture of the mucus and multi-cellular epithelium layer. Such models may result in an improved understanding of a drug’s intestinal permeability mechanism(s). Nevertheless, these newer models require validation with larger sets of drugs having known intestinal absorption before they can be routinely utilized to estimate human intestinal drug absorption.

KEYWORDS:

• Permeability
• cell models
• Caco-2 cells
• co-culture
• iPSC
• microfluidic systems

Article highlights

• A selection of in vitro cell-based assays are available to predict human intestinal drug absorption.

• Caco-2 and MDCK cell models are the most well known with demonstrated relationships between extent of absorption and experimental permeability values.

• Advancements to Caco-2 cell models include accelerated culture times, automation, co-cultures and 3-D cultures with other cell lines.

• Models with primary human intestinal epithelial cells and induced pluripotent stem cells are being developed to measure drug permeability.

• Microfluidic systems with Caco-2 cells provide a dynamic setting to better mimic the in vivo intestinal environment.

• In drug discovery and development, the cell lines allow for greater throughput in predicting intestinal permeability while newer models may improve the understanding of drug absorption mechanisms.

This box summarizes key points contained in the article.

Acknowledgments

The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency endorsement, determination, or policy.

Declaration of Interest

D Volpe has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.