Scientific Reports: Creating an Effective Rat Duodenal Monolayer Model with Barrier Function for ADME Assays using Rat Organoids
Introduction:
In the field of drug discovery and development, it is crucial to assess the absorption, distribution, metabolism, and excretion (ADME) properties of potential drug candidates. One of the key aspects of ADME assays is the evaluation of drug absorption in the gastrointestinal tract. To accurately predict drug absorption in humans, it is essential to develop reliable in vitro models that mimic the physiological conditions of the human gastrointestinal tract. In recent years, organoids have emerged as a promising tool for creating such models. This article focuses on the creation of an effective rat duodenal monolayer model with barrier function for ADME assays using rat organoids.
Rat Organoids:
Organoids are three-dimensional structures derived from stem cells that self-organize and mimic the structure and function of specific organs. Rat organoids, specifically those derived from intestinal stem cells, have gained significant attention due to their ability to recapitulate the complex architecture and cellular diversity of the intestine. These organoids can be cultured in vitro and used as a model system to study various aspects of intestinal biology, including drug absorption.
Creating a Rat Duodenal Monolayer Model:
To create an effective rat duodenal monolayer model, several steps need to be followed. First, rat intestinal stem cells are isolated from the duodenum and cultured in a specialized medium that promotes their growth and differentiation into organoids. These organoids can be expanded and maintained in culture for an extended period.
Next, to generate a monolayer model, the organoids are dissociated into single cells and seeded onto a permeable membrane support. The membrane support is typically made of a porous material that allows the exchange of nutrients and gases while providing a physical barrier between the apical and basolateral compartments. The cells are then allowed to grow and differentiate on the membrane support, forming a monolayer that mimics the epithelial lining of the duodenum.
Barrier Function Assessment:
One of the critical features of an effective duodenal monolayer model is its barrier function. The monolayer should exhibit tight junctions between adjacent cells, preventing the paracellular movement of molecules. To assess the barrier function, various techniques can be employed. One commonly used method is the measurement of transepithelial electrical resistance (TEER) using a volt-ohm meter. TEER provides an indirect measure of the tightness of the monolayer, with higher resistance indicating a more intact barrier.
Another important aspect of the barrier function assessment is the evaluation of drug transport across the monolayer. This can be done by measuring the apical-to-basolateral and basolateral-to-apical transport of specific drug molecules using techniques such as liquid chromatography-mass spectrometry (LC-MS). By quantifying the drug transport, researchers can determine the permeability and efflux properties of the monolayer, providing valuable information for ADME assays.
Applications in ADME Assays:
The rat duodenal monolayer model with barrier function has significant applications in ADME assays. It can be used to assess drug absorption, metabolism, and efflux in a controlled and reproducible manner. By studying drug transport across the monolayer, researchers can gain insights into the mechanisms underlying drug absorption and identify potential drug-drug interactions or efflux transporter-mediated drug resistance.
Furthermore, this model can be utilized to evaluate the impact of various factors on drug absorption, such as pH, formulation, and co-administration with other drugs. By incorporating physiological parameters into the model, researchers can better predict drug behavior in humans and optimize drug candidates for improved bioavailability.
Conclusion:
The creation of an effective rat duodenal monolayer model with barrier function using rat organoids provides a valuable tool for ADME assays. This model allows researchers to study drug absorption in a controlled and physiologically relevant environment, providing insights into drug behavior and aiding in the development of safe and effective drugs. With further advancements in organoid technology, the potential for creating more sophisticated and accurate in vitro models for ADME assays is promising.
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