Absorption paracellular

Although a portion of the nutrients released from feedstuff s is absorbed by diffusing across the apical membrane of enterocytes or through the junctional complexes of adjacent enterocytes (paracellular absorption), the majority of nutrients are absorbed from the lumen of the GIT by carrier proteins that are inserted into the apical membrane of enterocytes and colonocytes. 

Keywords Nasal absorption Air-interfaced culture Absorption enhancer Liquid-covered culture Mucociliary clearance Nasal epithelial cell mono-layer Paracellular absorption Tight junction Transcelluar absorption Drug transport... 

Compounds can cross biological membranes by two passive processes, transcellu-lar and paracellular mechanisms. For transcellular diffusion two potential mechanisms exist. The compound can distribute into the lipid core of the membrane and diffuse within the membrane to the basolateral side. Alternatively, the solute may diffuse across the apical cell membrane and enter the cytoplasm before exiting across the basolateral membrane. Because both processes involve diffusion through the lipid core of the membrane the physicochemistry of the compound is important. Paracellular absorption involves the passage of the compound through the aqueous-filled pores. Clearly in principle many compounds can be absorbed by this route but the process is invariably slower than the transcellular route (surface area of pores versus surface area of the membrane) and is very dependent on molecular size due to the finite dimensions of the aqueous pores. 

Tab. 6.1 Correlation between paracellular absorption and renal clearance.

It is well established today that drug absorption through the alimentary canal walls is a complex event, which involves, in many cases, parallel or sequent microprocesses at the apical membrane of the absorptive cell (enterocyte) or between them (paracellular absorption). In addition to the various types of diffusion processes across the enterocyte membrane, numerous specific proteins—transporters and efflux pumps—are involved in the intricate drug absorption process. In the following sections the various epithelial tissues of the different organs of the GI tract will be looked at briefly. A review of major drug absorption mechanisms across epithelial cells, as they are customary today will follow. 

FIGURE 1.11 A scheme of the various absorption routes across the intestinal epithelium and cellular barriers to xenobiotics absorption. A, Transcellular absorption (plain diffusion) B, paracellular absorption C, carrier-mediated transcellular absorption D, facilitated diffusion E, the MDR and P-gp absorption barrier and F, endocytosis. (From Hunter, J. and Hirst, B.H., Adv. Drug Deliv. Rev., 25, 129, 1997. With permission.)... 

Below or at the CMC In this case it was assumed that the paracellular absorption rate constant, ko2, was the same as k.2 in Eq. (2), whereas the membrane absorption rate constant, koi, was calculated as was kj in colon tests from Eq. (4). Accordingly, the global ka value should be ... 

Barriers to Paracellular Absorption 3.4.1 The Tight Junctional Complex... 

Bypassing intestinal transmembrane transporters mainly by a paracellular absorption would avoid or limit exposure of the substrate to these efflux pumps. Improved paracellular uptake can be achieved by using fatty acids, calcium chelators such as EDTA, papain, bromelain, surfactants, chitosans, polyacrylic acid or thiolated polymers. 

A temporary widening of the tight junctions of cultured cells, which coincided with an increase in the rate of absorption of the applied drug, insulin, has been observed in the presence of starch microspheres. It is likely that the dry starch microspheies took up water from the cells causing them to dehydrate and shrink resulting in a separation of the intercellular junctions. Should this be the case, it provides evidence for the paracellular absorption of insulin. 

Paracellular absorption. This is usually thought to occur through the junctional complex between two cells. The evidence for this route of absorption is not very convincing in case of the lungs. Molecules smaller than 40kDa may enter via the junctional pores. 

The volume of the luminal solution, which may change as a result of absorption or secretion of water, is an important parameter when applying in situ techniques. A non- or low-absorbable volume marker, such as radiolabeled polyethyleneglycol 4000 or a fluorescent marker (lucifer yellow), and a marker of paracellular absorption (mannitol) need to be added and monitored as internal standards. 

Figure 9.2 Possible pathways for intestinal absorption of a compound (a) transcellular passive diffusion (b) carrier-mediated transport (c) paracellular absorption (d) entry limited by P-gp, an efflux transporter ...

Zhou, S.Y., et al. Regulation of paracellular absorption of cimetidine and 5-Aminosalicylate in rat intestine. 

Apart from the predominant lymphatic drug absorption mechanism, other possible mechanisms of drug transport through intestinal barriers include transcellular and paracellular absorption of drug molecules, inhibition of P-gp and/or CYP450 to accumulate the intracellular drug concentration, and production of lipoprotein/ chylomicron. 

---