Paracellular permeation drugs

M Tomita, M Shiga, M Hayashi, S Awazu. Enhancement of colonic drug absorption by the paracellular permeation route. Pharm Res 5 341-346, 1988. 

The paracellular permeation pathway in the intestinal cell monolayer models is often limited. Therefore these models are not suitable for predicting permeability of paracellularly absorbed compounds. The average pore radius in Caco-2 cells (<6 A) is more representative of the colon than the small intestine (8-13 A)and paracellular transport can be up to 100-fold lower in Caco-2 cells than in the small intestine. Investigation of a rat intestinal cell line 2/4/Al, which forms polarized cell mono-layers and has an average pore radius (9 A) more representative of the small intestine, showed improved prediction of oral absorption for incompletely absorbed drugs [24, 25]. 

Another human colonic cancer cell line is T84, which forms monolayers that are even tighter than those of the Caco-2. It has been described as resembling a colonic crypt cell phenotype. Hence, these cells have been used mainly in studies of epithelial ion secretion and are generally not considered to be adequate for drug transport studies, particularly with respect to carrier-mediated processes [13, 91, 92]. The rat intestinal epithelial cell line IEC-18 has been evaluated as a model to study small intestinal epithelial permeability. This cell line, which forms very leaky monolayers, was proposed to be a better model than the Caco-2 monolayers for evaluating the small intestinal paracellular permeation of hydrophilic molecules [93]. Importantly, the leaky tight junctions of the IEC-18 cells are a result of an undeveloped paracellular barrier lacking the perijunctional actin belt. In addition, the IEC-18 cells have minute expression of transporters [91, 93]. 

Upon examination of the columns of Pe and PM values for each drug in Table 16, one discovers that the influence of PF is minimal. Therefore, Pe = PM, i.e., permeation of the drugs across the ABL/cell monolayer/filter barriers is governed by the cell monolayer. The remaining questions are (1) To what extent is the transmonolayer diffusional process of uncharged and cationic species gated by the transcellular and paracellular routes and (2) What are the governing factors ... 

There are two pathways by which a drug molecule can cross the epithelial cell the transcellular pathway, which requires the drug to permeate the cell membranes, and the paracellular pathway, in which diffusion occurs through water-filled pores of the tight junctions between the cells. Both the passive and the active transport processes may contribute to the permeability of drugs via the transcellular pathway. These transport pathways are distinctly different, and the molecular properties that influence drug transport by these routes are also different (Fig. 

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). 

Cheek, J.M., Kim, K.-J., and Crandall, E.D., NOj decreases paracellular resistance to ion and solute flow in alveolar epithelial monolayers, jcp. Lung Res., 16 561-575 (1990). Rangachari, P.K., Prior, T., and MeWade, D., Epithelial and mucosal preparations from canine eolon responses to substanee P, J. Pharmacol Exp. Ther., 254 1076-1083 (1990). Tomita, M., Hayashi, M., Toshiharu, H., and Awazu, S., Enhancement of colonic drug absorption by the transcellular permeation route, Pharm. Res., 5 786-789 (1988). 

Poor intestinal absorption of a potential drug molecule can be related to poor physicochemical properties and/or poor membrane permeation. Poor membrane permeation could be due to low paracellular or transcellular permeability or the net result of efflux from transporter proteins including MDRl (P-gp) or MRP proteins situated in the intestinal membrane. Cell lines with only one single efflux transporter are currently engineered for in vitro permeability assays to get suitable data for reliable QSAR models. In addition, efforts to gain deeper insight into P-gp and ABC on a structural basis are going on [131, 132]. 

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