Cell Models of the GI Tract

FIGURE 16.3 Challenges with in vitro models of the GI tract. Successive improvements in cell isolations and culture and understanding the molecular mechanisms of differentiation and microfluidic technology are improving our abihty to model the Gl tract in vitro. 

The Sartorius Absorption Model (26), which served as the forerunner to the BCS, simulates concomitant release from the dosage form in the GI tract and absorption of the drug through the lipid barrier. The most important features of Sartorius Absorption Model are the two reservoirs for holding different media at 37°C, a diffusion cell with an artificial lipid barrier of known surface area, and a connecting peristaltic pump which aids the transport of the solution or the media from the reservoir to the compartment of the diffusion cell. The set-up is shown in Figures 7a and b. 

The poor oral bioavailability of drugs is generally assumed to be due to physio-chemical problems, which result in poor solubility in the gastrointestinal (GI) tract or difficulty in diffusion through small intestine epithelial membrane. Furthermore, the biochemical process also contributes to oral bioavailability. The in vitro cell culture models of the intestinal epithelial cell barrier have evolved to become widely used experimental devices. 

Combining cell types in vitro by coculturing is one way to increase the long-term viability as well as complexity of in vitro models, and to this end, cocultures of intestinal epithelial cells with myofibroblasts, immune cells, or bacteria have been utilized to model the interactions between epithelial cells and others within the GI tract. Susewind et al. (2015) investigated the effect of coculturing Caco-2 cells... 

Physiological Buffer Systems Recently, a lot of efforts have been made on how to increase the biorelevance of the Caco-2 model [63, 47, 64, 65,105], Historically, the media used for Caco-2 experiments were buffered at pH 7.4 on both sides of the monolayer. The pH in the cellular interstice and blood compartment is known to be 7.4. However, the pH in the upper GI tract under fasted conditions ranges from 5.0 to 6.5, with an acidic microclimate existing just above the epithelial cell layer estimated to be between 5.8 and 6.3 [90], The pH of the apical medium can have a critical effect on the transport of drugs, especially for drugs with a pKa close to 7, or when pH-dependent transporters are involved. 

Because poor bioavailability represents one of the principal causes of compound failure, absorption and metabolism assays feature prominently in lead optimization screens. As oral administration represents the ideal route of drug delivery, models that predict low absorption across the gastrointestinal (GI) tract are commonly employed. Caco-2 cell assays have been... 

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