paracellular pathway

The transfer of substances across an epithelium by passing through the intercellular space between the cells.

The molecules are mainly restricted by tight junctions, a network of transmembrane proteins forming pores of ~8 Å diameter and connected to the actomyosin ring through zonula occludens proteins. Under steady-state condition, these highly regulated structures allow the diffusion of ions (mostly cations) and inert molecules of small size (molecular weight ＜600 Da, mannitol, lactulose) often used as permeability markers. The tight junctions have a net negative charge, and are believed to preferentially transport positively charged molecules. Tight junctions in the intestinal epithelium are also known to be size-selective, such that large molecules (with molecular radii greater than about 4.5 Å) are excluded. The permeability can be increased in various pathological situations in which molecules of higher molecular weight can diffuse nonspecifically across the epithelial layer.

In most mammals, intestinal absorption of nutrients is thought to be dominated by transcellular transport. Small birds and bats rely on the paracellular pathway for the majority of glucose absorption in the intestine. This has been hypothesized to compensate for an evolutionary pressure to reduce mass in flying animals, which resulted in a reduction in intestine size and faster transit time of food through the gut.

The paracellular pathway of transport is also important for the absorption of drugs in the gastrointestinal tract. It allows the permeation of hydrophilic molecules that are not able to permeate through the lipid membrane by the transcellular pathway of absorption. This is particularly important for hydrophilic pharmaceuticals, which may not have affinity for membrane-bound transporters, and therefore may be excluded from the transcellular pathway.

The blood-brain barrier is the major barricade to delivering drugs to the brain. Drug molecules can penetrate the biological barriers via the transcellular and paracellular pathways of the biological barriers. But the presence of tight junctions limits drug transport through the paracellular pathway.