Transcellular permeation enhancers

Generally, low molecular mass permeation enhancers can be divided into transcellular and paracellular permeation enhancers. On the one hand the potential of permeation enhancers to open the paracellular route of uptake can be determined by the reduction in the transepithelial electrical resistance (TEER) (enhancement potential = EP). On the other hand the potential of permeation enhancers to open the transcellular route of uptake can be determined by the lactate dehydrogenase (LDH) assay (LDH potential = LP). The parameter K = (EP—LP)/EP represents the relative contribution of the paracellular pathway. Consequently, a K value of 0 means predominantly transcellular and a K value of 1 means predominantly paracellular. Based on this classification system Whitehead and Mitragotri classified over 50 low molecular mass permeation enhancers showing that most of them are paracellular and only a few of them are transcellular permeation enhancers (2008). 

Transcellular permeation enhancers include surfactants, medium chain fatty acids, nonionic surfactants,38 sodium cholate and other bile salts,39 and many other surfactants. 

Tomita, M., Shiga, M., Hayashi, M., and Awazu, S., Enhancement of colonic drug absorption by the transcellular permeation route, Pharm. Res., 5 431-435 (1988). 

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). 

Swenson ES, Milisen WB, Curatolo W (1994) Intestinal permeability enhancement structure-activity and structure-toxicity relationships for nonylphenoxypolyoxyethylene surfactant permeability enhancers. Pharm Res 11 1501-1504 Tomita M, Hayashi M, Horie T, Ishizawa T, Awazu S (1988) Enhancement of colonic drug absorption by the transcellular permeation route. Pharm Res 5 786-789 Tomita M, Sawada T, Ogawa T, Ouchi H, Hayashi M, Awazu S (1992) Differences in the enhancing effects of sodium caprate on colonic and jejunal drug absorption. Pharm Res 9 648-653... 

Permeation enhancers improve the absorption of protein and peptides by increasing their paracellular and transcellular transports. An increase in paracellular transport is mediated by modulating the tight junctions of the cells, and an increase in transcellular transport is associated with an increase in the fluidity of the cell membrane. Chapter 2 describes in depth the various paracellular and transcellular transport pathways, which will not be discussed here. 

Transcellular transport Sorption promoters can be used to enhance the transcellular transport in the intestine, including bile salts and fatty acid esters. They tend to fluidize the lipid bilayer and enhance drug permeation across the membrane. 

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