Gastrointestinal tight junctions

The intrinsic barrier of the gastrointestinal epithelium is characterized by intercellular junctions at the apical (luminal) side of differentiated epithelial cells, the so-called tight junctions (TJ), and the maintenance of epithelial integrity based on the balance between cellular proliferation and cell death, as described above. Barriers against drug absorption by the intracellular and paracellular routes, their modulation, and maintenance will be discussed in the following, with the focus on the intestinal epithelium. 

Absorptive and secretory changes of the gastrointestinal mucosa and microscopic damage (tight junction / brush borders) are not examined by this method. 

The gastrointestinal barrier is considered to comprise two components the intrinsic barrier, composed of epithehal cells lining the digestive tube and the tight junctions that tie them together and the extrinsic barrier, consisting of secretions and other influences that are not physically part of the epithehum but which affect the epithelial cells and maintain their barrier function (Table 4.1). 

Tight junctions between epithelial cells seal the paracellular spaces and establish the basic gastrointestinal barrier. 

Absorption barriers are related to the permeability of drug molecules across the gastrointestinal membrane including the colonic membrane. There are two distinct mechanisms for molecules to cross the membrane via paracellular transport and transcellular transport (Fig. 5). Para-cellular transport involves only passive diffusion where the molecules pass through the tight junctions between the epithelial cells. In contrast, transcellular transport can occur by passive diffusion as well as by active transport, or endocytosis. In general, the hydrophilic molecules diffuse predominantly through the paracellular route, whereas the lipophilic... 

It is often possible to address function more specifically in in vitro assays, where functional parameters are usually very sensitive readouts of adverse effects. For example trans-epithelial electrical resistance (TEER) is a very sensitive marker of epithelial disturbances. TEER measures the barrier function of the entire mono-layer and is utilized to study functional disturbances of many epithelial/endothelial cell types including blood-brain barrier, pulmonary, renal, and gastrointestinal cells. Its sensitivity lies in the fact that only a small proportion of cell death has a very large impact on barrier function. Additionally, cell stress can interfere with the arrangement and population of tight junction proteins [16] thus, TEER can in certain conditions measure functional disturbances in the absence of cell death [13]. Also since TEER can be measured noninvasively, it is nondestructive and can be used to monitor the effects of treatment over days and weeks [13, 17]. For excitable cells, electrical activity has also been proven to be an extremely sensitive parameter of adverse drug reactions and microelectrode arrays have been employed successfully to monitor neurotoxicity in vitro [18]. Also, for contractile cells, such as cardiomyocytes, the use of impedance measurements to measure the effects of compounds on spontaneous contraction has been demonstrated to be a very sensitive functional monitoring parameter in vitro [19, 20], Admittedly, none of the aforementioned techniques are true biomarkers per se however, such measurements illustrate the fact that in vitro techniques allow certain possibilities that are not practically tenable in the whole body. 

A number of studies of the mucosal mechanisms of lithium absorption in the gastrointestinal tract have shown that lithium [28,29], and indeed other metals [30-32], transfers across the tract not by passage through the cell but by paracellular transport via the tight junctions and pericellular spaces. Cellular transport mechanisms and carriers identified in cells may thus exist only for the domestic requirements of the intestinal cells themselves, which in turn protect their own milieu interieur by, as far as practicable, avoiding accumulation of externally derived metals [33]. 

The gastrointestinal tract includes the oral cavity, the stomach, the small intestines, the large intestine, and the rectum. The entire system is lined with epithelial cells, which typically have tight junctions between them which are rel-... 

Drugs can cross the intestinal epithelial barrier in a number of ways. They may permeate either through the cell (transcellular) or between adjacent cells (para-cellular). Enterocytes have tight intercellular junctions that restrict paracellular transport to small hydrophilic molecules.7 These cells possess active and facilita-tive transporters for nutrients, as well as an array of efflux transporters [e.g., P-glycoprotein (P-gp) and related transporters] and enzymes (e.g., cytochrome P450 type 3A4) that restrict transcellular absorption. Transcytotic transport of macromolecules is possible, but compounds are often destroyed in lysosomes. With the exception of M-cells, transcytosis is not considered a major mechanism of the transcellular pathway for absorption of macromolecules across gastrointestinal epithelium.6... 

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