Paracellular transport extent

Another limitation of the Caco-2 monolayers is their colonic origin and tight paracellular pathway, which tend to lead to underestimations in permeability to paracellularly transported compounds [97]. This is likely to be correct for small compounds (MW < 150) - i.e., compounds smaller than normal drugs - but it remains to be seen to what extent the Caco-2 model gives false-negative predictions of the fraction absorbed for polar drugs of normal size in humans where para-... 

The enzymatic degradation of insulin was also shown to occur in the cytosol of alveolar cells, the pH optimum of the proteases being 7.4 [38]. To what extent intracellular proteases play a significant role in limiting the absorption of insulin is not clear, since the size of insulin likely allows paracellular transport over the alveolar epithelium. However, for proteins of higher molecular weight, that require transcellular transport, these proteases might certainly limit bioavailability. 

It has been shown that antibodies can reach the systemic circulation after oral administration, but only to a very small extent. The antibodies pass the intestinal epithelium not by passive transcellular but by receptor-mediated transcellular or paracellular transport. The Fc part of the antibody is responsible for the saturable receptor-mediated transport, especially IgG in breast-fed neonates. As the receptor is found primarily in the gastrointestinal tract of neonates, it was called Fc-Rn (Fc receptor neonatal). Apart from this location, Fc-Rn has also been discovered in other tissues such as the liver. Its role will be further discussed in Section 3.9.3. 

Permeation of mAbs across the cells or tissues is accomplished by transcellular or paracellular transport, involving the processes of diffusion, convection, and cellular uptake. Due to their physico-chemical properties, the extent of passive diffusion of classical mAbs across cell membranes in transcellular transport is minimal. Convection as the transport of molecules within a fluid movement is the major means of paracellular passage. The driving forces of the moving fluid containing mAbs from (1) the blood to the interstitial space of tissue or (2) the interstitial space to the blood via the lymphatic system, are gradients in hydrostatic pressure and/or osmotic pressure. In addition, the size and nature of the paracellular pores determine the rate and extent of paracellular transport. The pores of the lymphatic system are larger than those in the vascular endothelium. Convection is also affected by tortuosity, which is a measure of hindrance posed to the diffusion process, and defined as the additional distance a molecule must travel in a particular human fluid (i. e., in vivo) compared to an aqueous solution (i. e., in vitro). 

Although different opinions exist about the mechanism of strontium transport through the intestinal wall, the available data suggest that, in contrast to calcium, strontium is absorbed entirely via passive diffusion (= paracellular transport) [27-29]. In vitro [26] and in vivo experiments [30,31] have demonstrated that strontium is always absorbed to a lower extent than calcium, strontium/calcium ratios being approximately 0.45 0.50 [12,31]. The fraction absorbed from dietary intake was calculated to be 20% [32]. 

The extent to which the cell line is appropriate for drug metabolism and transport studies. If drug bidirectional transport studies are to be performed, the cell line needs to form monolayers with tight cell-cell junctions. If cell-cell junctions are loose, background (or nontransporter-dependent) paracellular drug transport... 

Calcium is absorbed both actively and passively throughout the small intestine and, to a small extent, in the colon. The active transcellular transport occurs in the duodenum and the passive paracellular process takes place in the jejunum and ileum. The chemical gradient and the sojourn time of the food passing through the intestine determine the movement of calcium that occurs by a passive process. The absorption of calcium in the colon becomes nutritionally significant under conditions of small intestine resection. 

---