Pathway para-cellular

JL Madara, JR Pappenheimer. Structural basis for physiological regulation of para-cellular pathways in intestinal epithelia. J Membrane Biol 100 149-164, 1987. 

The oral administration of large proteins and peptides is limited due to their low membrane permeability. These compounds are mainly restricted to the para-cellular pathway, but because of their polar characteristics and their size the pore of the tight junctional system is also highly restrictive. An additional transcellular pathway has therefore been suggested for these peptides, i.e., the transcytotic pathway, which involves a receptor-mediated endocytosis in Caco-2 cells [126],... 

The compounds can cross the membranes by passive processes, which depend only on the concentration gradient on both sides of the barrier, or by active ones, which are mediated by the interaction of the compound with a protein. The passive processes of the epithelial cells in the gastrointestinal tract include passive transport through the cell (trans-cellular pathway) or in the space between the cells (para-cellular pathway) [18]. 

A number of additional flavonoids have been smdied by using the Caco-2 cell model. These include the simplest form of the flavone class of flavonoids, the highly UpophUic unsubstimted flavone, which has been shown to diffuse readily across the enterocyte monolayer [45]. It also includes the highly polar hesperidin glycosides, which are suggested to be transported at a low rate via the para-cellular pathway [46]. Another citms flavonoid, 7-geranyloxycoumarin, has been shown to have a low transcellular permeation rate but was also shown to... 

Molecules with a large molecular weight or size are confined to the transcellular route and its requirements related to the hydrophobicity of the molecule. The transcellular pathway has been evaluated for many years and is thought to be the main route of absorption of many drugs, both with respect to carrier-mediated transport and passive diffusion. The most well-known requirement for the passive part of this route is hydrophobicity, and a relationship between permeability coefficients across cell monolayers such as the Caco-2 versus log P and log D 7.4 or 6.5 have been established [102, 117]. However, this relationship appears to be nonlinear and reaches a plateau at around log P of 2, while higher lipophilicities result in reduced permeability [102, 117, 118]. Because of this, much more attention has recently been paid towards molecular descriptors other than lipophilicity [86, 119-125] (see section 5.5.6.). The relative contribution between the para-cellular and transcellular components has also been evaluated using Caco-2 cells, and for a variety of compounds with different charges [110, 112] and sizes [112] (see Section 5.4.5). 

Chitosan and its derivatives have been applied to enhance the absorption of proteins (e.g., insulin) and polypeptides (e.g., buserelin). /V-Trimethyl chitosan chloride exhibits opening of the tight junctions of the intranasal and intestinal epithelial cells so that the transport of hydrophilic compounds is increased through the para-cellular transport pathway. The absorption-enhancing effect was concentration dependent and reversible and dependent on the integrity of the intercellular cell contact zone. 

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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