Drug Screening, Oral Bioavailability and Regulatory Aspects: A Need for Human Organoids

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. Caco2 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.

Progress of research on tumor organoids: A bibliometric analysis of relevant publications from 2011 to 2021

“…The data from cell and animal models related to intestinal nutrient absorption, metabolism and oral bioavailability of drugs have poor accuracy due to tumor heterogeneity and species differences. In contrast, intestinal organoids are used to examine different aspects of bioavailability, including drug distribution, individual differences, and high-throughput screening ( 32 ). Furthermore, the establishment of organoid models for the liver, kidney and blood-brain barrier meet the basic requirements for evaluating the different pharmacological aspects of drugs ( 33 ).…”

Unraveling the mystery of efficacy in Chinese medicine formula: New approaches and technologies for research on pharmacodynamic substances

“…7 ). Currently, the effects of the matrix and vascular system have not been considered in the current organoid cultures ( Zietek et al, 2021 ). Organoids will play a beneficial role in the study of disease mechanisms as an ideal model for the evaluation of active ingredients.…”

Complex in vitro 3D models of digestive system tumors to advance precision medicine and drug testing: Progress, challenges, and trends

“…The in silico model is complementary to traditional in vitro and in vivo modeling. Therefore, combining the organoid and microfluidic/chip models with in silico approaches can precisely predict the efficacy and toxic side effects of drugs and minimize costly preclinical experiments (Zietek, Boomgaarden, & Rath, 2021). Lewin et al constructed a microfluidic model of infiltration of T cells into intestinal mucosa, which recapitulates T cell bispecific antibody (TCB)-mediated T-cells activation and epithelial cells killing (Lewin et al, 2022).…”