Epithelial barriers absorption

Tukker JJ (2002) Characterization of transport over epithelial barriers. In Lehr CM (Ed) Cell Culture Models of Biological Barriers. In-vitro Test Systems for Drug Absorption and Delivery. Taylor and Francis, London, pp 52-61. 

There are two routes potentially involved in drug absorption across the nasal epithelial barrier the transcellular and paracellular routes [20], Several experimental evidences dealing with the mechanism of transnasal permeation support the existence of both lipoidal pathyway (i.e., transcellular route) and an aqueous pore pathway (i.e., paracellular route). 

In Vitro Models of the Alveolar Epithelial Barrier for Drug Absorption Studies... 

Water-soluble substances will readily dissolve into the gastrointestinal fluids however, absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. If the molecular weigjit is low (less than 200), the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. 

Even if dimers and trimers are stable under GIT conditions and absorbed in their native form as seen for the monomers, the amount crossing the epithelial barrier of the small intestine and being further excreted in urine must be very low. The major part of the ingested procyanidins must reach the colon where an abundant microflora can metabolize them into smaller molecules, which are more readily absorbed. The general absorption and metabolism pathways of procyanidin monomers to oligomers in the GIT, from their ingestion to microbial metabolism, are summarized in Figure 2.5. 

While it might seem reasonable to use a generic marker such as polyethylene glycol, which is completely eliminated without absorption (used to verify integrity of the epithelial barrier), it is important for the marker to have physical properties similar to the nutrient in question because of the complexity of the postprandial intestinal milieu - a thick slurry of mixed micelles, oil and water phases, and suspended particles. The marker should partition among the phases similarly to the analyte of interest and should have similar intestinal transit times. Thus, sugars must be used to trace sugars, sterols to trace sterols, etc. 

The primary cell culture model is a more valid model for the study of absorption and transport processes of a drug via the pulmonary route. It provides a tight epithelial barrier with morphological and functional properties resembling those of the in-vivo condition. Primary alveolar epithelial cells from rats [39], rabbits [40] and humans [41] which display morphological and biochemical characteristics similar to the native epithelium have been isolated and can be used for drug transport studies. 

The absorption of drugs, although dependent on the particular absorption site in question, is often controlled by the same set of epithelial barriers, which include ... 

From Figure 1.3 it can be seen that in order to reach the underlying blood capillaries to be absorbed, the drug must pass through at least two epithelial membrane barriers (the apical and basolateral epithelial cell membranes) and also the endothelial membrane of the capillaries. In some cases, for example in stratified epithelia such as that found in the skin and buccal mucosa, the epithelial barrier comprises a number of cell layers rather than a single epithelial cell. Thus the effective barrier to drag absorption is not diffusion across a single membrane as described above, but diffusion across the entire epithelial and endothelial barrier, which may comprise several membranes and cells in series. 

The inclusion of enzyme inhibitors in a formulation may help to overcome the enzymatic activity of the epithelial barrier. Work in this field has concentrated on the use of protease inhibitors to facilitate the absorption of therapeutic peptides and proteins. Protease inhibitors demonstrating potential to increase... 

The epithelium is supported underneath by lamina propria and a layer of smooth muscle called muscularis mucosa (3-10 cells thick). These three layers, i.e., the epithelium, lamina propria, and muscularis mucosa, together constitute the intestinal mucosa.On the apical surface, the epithelium along with lamina propria projects to form villi. The cell membranes of epithelial cells that comprise the villi contain uniform microvilli, which give the cells a fuzzy border, collectively called a brush border. These structures, although greatly increase the absorptive surface area of the small intestine, provide an additional enzymatic barrier since the intestinal digestive enzymes are contained in the brush border. In addition, on the top of the epithelial layer lies another layer, the UWL, as previously described. The metabolic and biochemical components of the epithelial barrier will be discussed. 

Although the adult intestine provides a more effective epithelial barrier than that in newborns, evidence indicates that small quantities of intact proteins are transported across intestinal epithelial cells. There are two possible mechanisms associated with the absorption of intact proteins endocytosis and transport through the epithelium of Peyer s patches. 

Epithelial barrier models for the skin [48,49], respiratory tract [50], BBB, and intestine [39] are constructed to study and predict the absorption, penetration, and metabolism of drugs or environmental toxins through these barriers. All the models are physically tight structures, and generally involve cells cultured at the air-liquid interface on porous membrane support, such as a porous polycarbonate filter. The use of a permeable support allows cells to be grown in a polarized state under more natural conditions promote Cell differentiation and enhance cell functions. 

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... 

Upon intranasal administration, a drug is not as susceptible to dilution and first-pass effects as in oral delivery.46 47 The nasal route may also be an effective means of delivering drugs to the brain 46 Barriers to nasal delivery include the enzymes of the nasal mucosa, the epithelial barrier, the mucus layer, and limited absorption time resulting from mucociliary clearance.48... 

Once past the epithelial barrier, the entry of macromolecules into the blood is easier to predict. Venules and lymph vessels provide the major pathway for absorption. Direct absorption may also occur across the tight junctions of capillary endothelium. 

May be related to dietary restriction or Gl absorption problems. Deficiencies may serve to enhance the pathogenic potential of the Candida inhabitants, alter host defense mechanisms, or change epithelial barrier integrity. 

As described previously, peptides and proteins co-administered with absorption enhancers and protease inhibitors promote passage through gastrointestinal epithelial barriers and reduce degradation in the gut [1]. In this way, these compounds can en-... 

The rate and extent of intestinal permeation is dependent on the physicochemical properties of the compound (see Sections 16.1.2 and 16.4.3) and the physiological factors. Drugs are mainly absorbed in the small intestine due to its much larger surface area and less tight epithelium in comparison to the colon [17]. The permeation of the intestine may be affected by the presence of an aqueous boundary layer and mucus adjacent to cells, but for a majority of substances the epithelial barrier is the most important barrier to drug absorption. The lipoidal cell membrane restricts the permeability of hydrophilic and charged compounds, whereas large molecules are restricted by the ordered structure of the lipid bilayer. 

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