Trans-cellular

The perturbation of monolayers with agents (e.g., disodium ethylenediamine tetraacetate, Ca+2-free medium, sodium citrate, cytochalasin D) to open tight junctions and the effect on the transmonolayer flux of permeants are addressed in this section. It has been observed that permeants taking predominantly the trans-cellular route are not affected by perturbants of the paracellular route, compared to extracellular or relatively hydrophilic permeants (Artursson and Magnusson, 1990). Let us put these general observations into a quantitative intepretation in the light of the transmonolayer kinetic studies of steroids in this section and of paracellular permeants in Section III. There are three cases to consider (1) ABL-controlled permeants, (2) monolayer-controlled permeants transported principally by the transcellular route, and (3) monolayer-controlled permeants for which the paracellular route dominates. 

Knowing the fraction of nondissociated solutes at pH 7.4 and 6.5, one obtains the permeabilities of the various molecular species across the parallel trans-cellular and paracellular routes of the cell monolayer. Hence, restating Eq. (83) as... 

It should be mentioned that the placental villous fragments can be used to measure uptake into the syncytiotrophoblast layer but they cannot be used for trans-cellular transport studies. If the transporter is expressed in the microvillous border membrane, the effects of various factors on transporter function can be determined. Another disadvantage is that the villous fragments may be heterogenous in composition and hence, uptake experiments may not be reflective of syncytiotrophoblast uptake alone. 

Cerebrospinal fluid (liquor cerebrospinalis, CSF) belongs to the class of trans-cellular fluids. It has a low cell count and is hypooncotic and isoosmotic, even with the different composition of ions relative to plasma (lower concentration of Na+, K+, Ca +, inorganic phosphates, and HCO in contrast to a higher concentration of Mg + and CC). The ion composition of CSF is stable changes occur with large plasmatic variations. 

Fig. 12.1 Schematic representation of the three transepithelial intestinal pathways (a) trans-cellular active transport, (b) transcellular passive transport, (c) paracellular transport (Fasano...

The compounds can cross the membranes by passive processes, which depend only on the concentration gradient on both sides of the barrier, or by active ones, which are mediated by the interaction of the compound with a protein. The passive processes of the epithelial cells in the gastrointestinal tract include passive transport through the cell (trans-cellular pathway) or in the space between the cells (para-cellular pathway) [18]. 

Lacombe, O. Woodley, J. Solleux, C. Delbos, J. M. Boursier-Neyret, C. Houin, G. Localisation of drug permeability along the rat small intestine, using markers of the paracellular, trans-cellular and some transporter routes, Eur.f Pharm. Sci. 2004, 23 (4-5), 385-391. 

Tomita, M. Hayashi, M. Horie, T. Ishizawa, T. Awazu, S. Enhancement of colonic drug absorption by the trans-cellular permeation route. Pharm. Res. 1988, 5 (12), 786-789. 

Figure 1 Parallel pathways of intestinal absorption (1) paracellular pathway, (2) trans-cellular pathway, (2a) carrier-mediated, (2b) passive diffusion, (2c) receptor-mediated endocytosis, and (3) mediated efflux pathway. (From Ref. 30.)...

The microvillus membrane of the absorptive cell has a thickness of 9.5-11.5 nm, which is somewhat thicker than normal biological membranes. It is folded into microvilli (about 200,000/mm2 in the human jejunum [11]), and increases the surface of the intestine by a factor of 20. Microvilli contract, and, during contraction the fibers in the core slide down toward the underlying terminal web. In this region, the movement of drugs and other molecules will not only be diffusive but also agitative. Molecules passing the membrane are absorbed by the trans-cellular pathway. 

Chemistry control of intestinal permeability via passive tran -cellular processes is poor. The good news is that, in general, poor permeability is not a problan in combinatorial libraries. One really has to go out of one s way to introduce enough polar functionality in a combinatorial compound to... 

Kvietys, P.R. and Sandig, M. (2001). Neutrophil diapedesis paraceUular or trans-cellular News Physiol. Sd. 16,15-19. 

An additional cause is an age-related reduced activity of cystathionine-p-synthase (and possibly of other enzymes involved) and a substantial decrease in the amount of vitamin B12 bound to TC II, responsible for trans-cellular B12 in- and out-transportation (Herrmann et al. 2003a). According to Obeid et al. (2005), vitamin B12 supra-physiological doses are probably necessary to deliver a sufficient amount of vitamins to cells via mechanisms largely independent of holoTC receptors but still unknown. 

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