Abstract
The intestinal epithelium critically contributes to oral bioavailability of drugs by constituting an important site for drug absorption and metabolism. In particular, intestinal epithelial cells (IEC) actively serve as gatekeepers of drug and nutrient availability. IECs’ transport processes and metabolism are interrelated to the whole-body metabolic state and represent potential points of origin as well as therapeutic targets for a variety of diseases. Human intestinal organoids represent a superior model of the intestinal epithelium, overcoming limitations of currently used in vitro models. Caco-2 cells or rodent explant models face drawbacks such as their cancer and non-human origin, respectively, but are commonly used to study intestinal nutrient absorption, enterocyte metabolism and oral drug bioavailability, despite poorly correlative data. In contrast, intestinal organoids allow investigating distinct aspects of bioavailability including spatial resolution of transport, inter-individual differences and high-throughput screenings. As several countries have already developed strategic roadmaps to phase out animal experiments for regulatory purposes, intestinal organoid culture and organ-on-a-chip technology in combination with in silico approaches are roads to go in the preclinical and regulatory setup and will aid implementing the 3Rs (reduction, refinement and replacement) principle in basic science.
Highlights
Oral bioavailability refers to the extent a substance or drug becomes completely available to systemic circulation or to its intended biological destination(s) via the oral route [1]
In the GI tract, the intestinal epithelium crucially contributes to oral bioavailability by constituting an important site for drug absorption, distribution, metabolism, and excretion (ADME)
Expression of enzymes and transporters involved in drug metabolism and xenobiotic defense including cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltransferase isoforms (UGTs) and ATP binding cassette (ABC) transporters, e.g., the multidrug efflux pump P-glycoprotein (P-gp), give rise to the concept of the intestinal epithelium as a pharmacogenetic barrier [2]
Summary
Oral bioavailability refers to the extent a substance or drug becomes completely available to systemic circulation or to its intended biological destination(s) via the oral route [1]. Beyond constituting a physical barrier separating the host from its environment including the intestinal microbiota, IECs actively serve as gatekeepers of nutrient availability and metabolic health for the whole organism. Despite this importance, many aspects of nutrient absorption, enterocyte metabolism, and drug bioavailability are still unknown, e.g., the underlying causes of fructose malabsorption remain elusive [7]. We briefly describe the role of IECs for oral bioavailability and discuss the (future) contribution of human intestinal organoid culture and organ-on-a-chip technology for basic research, drug screening and the regulatory setup, illustrating the advantages of a human-based model for drug development
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