Paracellular 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). 

Jonker, C., Hamman, J. H., Kotze, A. F. (2002). Intestinal paracellular permeation enhancement with quaternized chitosan In situ and in vitro evaluation, Int I. Pharm.. 238,205-213. 

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

Tsutsumi K, Kevin Li S, Hymas RV, Teng C-L, Tillman LG, Hardee GE, Higuchi WI and Ho NFH (2008) Systematic studies on the paracellular permeation of model permeants and oligonucleotides in the rat small intestine with chenodeoxycholate as enhancer. J Pharm Sci 97(l) 350-367... 

Mucus also appears to be a barrier to the permeation enhancing effect of polymeric or monomeric absorption enhancers. In the aforementioned TMC studies, the enhancement effect (enhancement ratio = permeation rate of the drug in the presence of polymer vs. permeation rate of the drug alone) was higher in vitro (Caco-2 cells no mucus secretion) than the absorption enhancement in vivo. Meaney and O Driscoll studied the effect of mucus on the permeation properties of a micellar system consisting of sodium taurocholate in a coculture of Caco-2 and Ht29GlucH (mucin-secreting) cells. They found that the effect of bile salts on the permeation of hydrophilic paracellular markers was increased in the cocultures that were pretreated with the mucolytic compound A/-acetylcysteine. 

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. 

Low molecular mass (LMM) permeation enhancers include various classes of substances. All molecules that interact with the membrane lipids or proteins and lead to membrane perturbation, in principle, be applied and may be helpful to guide drugs through the cells of the mucosa. However, the paracellular route... 

---