The Past, Present and Future of Intestinal In Vitro Cell Systems for Drug Absorption Studies

Abstract

The intestinal epithelium acts as a selective barrier for the absorption of water, nutrients and orally administered drugs. To evaluate the gastrointestinal permeability of a candidate molecule, scientists and drug developers have a multitude of cell culture models at their disposal. Static transwell cultures constitute the most extensively characterized intestinal in vitro system and can accurately categorize molecules into low, intermediate and high permeability compounds. However, they lack key aspects of intestinal physiology, including the cellular complexity of the intestinal epithelium, flow, mechanical strain, or interactions with intestinal mucus and microbes. To emulate these features, a variety of different culture paradigms, including microfluidic chips, organoids and intestinal slice cultures have been developed. Here, we provide an updated overview of intestinal in vitro cell culture systems and critically review their suitability for drug absorption studies. The available data show that these advanced culture models offer impressive possibilities for emulating intestinal complexity. However, there is a paucity of systematic absorption studies and benchmarking data and it remains unclear whether the increase in model complexity and costs translates into improved drug permeability predictions. In the absence of such data, conventional static transwell cultures remain the current gold-standard paradigm for drug absorption studies.

Organoids to Study Intestinal Nutrient Transport, Drug Uptake and Metabolism – Update to the Human Model and Expansion of Applications

“…Hence, radiolabeled substrates were simply added to the culture plates, keeping the organoids in their 3-dimensional environment (a dome of laminin-rich gel) ( Zietek et al, 2015 ). As species-specific differences might result in misleading outcomes ( Youhanna and Lauschke, 2020 ), we validated experimental procedures for human intestinal organoids, allowing for tackling human-specific research questions. After confirming translocation of 4 kDa FITC-dextrans also into the lumen of human organoids ( Supplementary Figure 2A ), we applied the experimental procedures established in murine intestinal organoids ( Supplementary Figure 2B ) to human organoids.…”

Physiological Shear Stress Enhances Differentiation, Mucus-Formation and Structural 3D Organization of Intestinal Epithelial Cells In Vitro

“…Notwithstanding the extensive developments in the culture of primary intestinal cells as organoids or monolayers, intestinal models based on immortalized cells currently remain the most commonly used systems for routine applications due to their robustness, scalability, reproducibility and cost-effectiveness, with Caco-2 cells being the most widely used cell line [14,15]. These cells are derived from a human colorectal adenocarcinoma and exhibit several properties of enterocytes, including the formation of tight junctions and the expression of drug transporters as well as typical metabolic enzymes [16].…”

Cerebral Organoids Derived from a Parkinson’s Patient Exhibit Unique Pathogenesis from Chikungunya Virus Infection When Compared to a Non-Parkinson’s Patient

“…Ongoing advances with stem-cell research have provided a platform for producing specific cell types or organoids from human stem cells. Within the last few years, significant advances in human health have been made using stem cells and organoids [ 45 , 46 , 47 , 48 , 49 ]. Human stem cells and organoids are emerging as a useful tool for virus research [ 50 , 51 ].…”