Paracellular permeation

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

Figure 11 Change in paracellular permeation of sucrose and mannitol across MDCK cell monolayers following addition of 1 pg/mL cytochalasin D.

The rat intestinal cell line IEC-18 has been evaluated as a model to study small intestinal epithelial permeability. This cell line forms very leaky monolayers with TER of 50 n cm2 and permeability to mannitol of 8 x 10-6 cm s 1. The IEC-18 model was proposed to be a better model than the Caco-2 monolayers for evaluating the small intestinal paracellular permeation of hydrophilic molecules. However, the leakier paracellular pathway is related to the poor differentiation level of the cells and an undeveloped paracellular barrier lacking peri-junctional actin-belt. In addition, due to the poor differentiation the cells have minute expression of transporters and are therefore not useful for studies of carrier-mediated transport [82, 84]... 

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]. 

The superficial two to three cell layers of the corneal and conjunctival epithelium are the main barrier for the permeation of topically applied compounds. In this rate-limiting cell layer, the transcellular permeation is dictated by the lipophilicity of the cell membrane whereas the paracellular permeation is limited by the paracellular pore size and density. Vesicular penetration (e.g., receptor- or endocytosis-mediated) of macromolecules across surface epithelium is possible [33], However, the proposed mechanism is energy consuming (e.g., incorporation into pinocytotic vesicles and phagosomes) and thus more feasible in cell lines with abundant intracellular energy sources like corneal endothelium and RPE [34-37]. 

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... 

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). 

III). The tight tissue boundaries include the intestinal wall, skin, cornea, conjunctiva, blood-brain barrier, placental barrier, and blood-retina barrier. In leaky tissue boundaries (e.g. fenestrated endothelia, sinusoidal vessels, and tissue boundaries disrupted by the disease states such as inflammation), the nanoparticulates may pass the barrier by paracellular permeation. In specific cases, receptor-mediated transcytosis may be possible... 

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. 

Permeation across the intestinal wall involves both passive and facilitated processes. Passive transport includes passive transcellular permeation and paracellular diffusion across cell junctions, while facilitated transport includes active influx and efflux processes that pump molecules in and out of the cells. In order to improve absorption of a molecule, engineering passive permeability is a preferred strategy over engineering affinity to an influx transporter. The expression levels of active transporters vaiy significantly between different tissues and individuals, and the specificities and expression levels vaiy among mammals, which decreases the ability to predict human PK based on animal studies. In contrast, passive membrane permeability basically works the same with any eukatyotic membrane, although there may be minor quantitative differences due to different membrane compositions. As paracellular permeation is mainly pertinent to small and polar molecules, passive membrane permeability, which is crucial to transcellular diffusion, is therefore one of the kty properties that needs to be optimized for developing bioavailable macrocycles. 

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