Transcellular space

The transcellular fluid includes the viscous components of the peritoneum, pleural space, and pericardium, as well as the cerebrospinal fluid, joint space fluid, and the gastrointestinal (GI) digestive juices. Although the transcellular fluid normally accounts for about 1% of TBW, this amount can increase significantly during various illnesses favoring fluid collection in one of these spaces (e.g., pleural effusions or ascites in the peritoneum). The accumulation of fluid in the transcellular space is often referred to as third spacing. To review the calculations of the body fluid compartments in a representative patient, see Patient Encounter 1. 

Extracellular fluid (ECF) is divided into smaller compartments. These spaces between the cells are called the interstitial space. The space is occupied by plasma and lymph, transcellular fluid, and fluid in the bone and connective tissues. This makes up 20% of body weight. About a third is plasma and two thirds of extracellular fluid is in the space between the cells. Transcellular fluid is also ECF but is found in the gastrointestinal (GI) tract, cerebrospinal space, aqueous humor, pleural space, synovial space, and the peritoneal space. Although fluid in the transcellular space is a small volume when compared with intracellular and extracellular compartments, the increase or decrease in volumes in transcellular spaces can have a dramatic effect on the fluid-electrolyte balance. 

In addition, the physical dimensions of the cells making up the monolayer should be considered. Cell shape can influence the relative contributions of the paracellular and transcellular pathways. For example, junctional density is greater in cells that are narrow or of small diameter than in cells that are wide or spread out on the substrate. The height of the cells can impact the path length traveled by a permeant, as will the morphology of the junctional complex and lateral space (Section m.B.2). It is unknown how the mass of lipid or membrane within a cell influences transcellular flux of a lipophilic permeant. 

Distinguishing between adsorption on to the cell surface and the actual transfer across the cell membrane into the cell may be difficult, since both processes are very fast (a few seconds or less). For fish gills, this is further complicated by the need to confirm transcellular solute transport (or its absence) by measuring the appearance of solutes in the blood over seconds or a few minutes. At such short time intervals, apparent blood solute concentrations are not at equilibrium with those in the entire extracellular space, and will need correcting for plasma volume and circulation time in relation to the time taken to collect the blood sample [30]. Nonetheless, Handy and Eddy [30] developed a series of rapid solution dipping experiments to estimate radiolabelled Na+... 

Cellular Cl- replenishment is maintained by a basolateral anion-exchanger (Cl /OH or Cr/HCOJ) or via the Na+/K+/2C1 co-transporter, whose activities are closely tied synergistically through action of Na+/K+-ATPase, K+ channels, and the IIC()7/Na+ co-transporter (with a 3 1 stoichiometry) that extrudes HCOJ [61]. Passive Cl- diffusion through the paracellular pathway can occur because of the greater mobility of Cl- than Na+ in the paracellular space ( <1.3) [13]. Electroneutrality is maintained by transcellular Na+ transport in the luminal to subluminal direction, accomplished by both the apical Na+/H+ exchanger (NHE-3) and a basolateral HCOJ/Na+ co-transporter (with a 3 1 stoichiometry). 

The most efficient rectal absorption enhancers, which have been studied, include surfactants, bile acids, sodium salicylate (NaSA), medium-chain glycerides (MCG), NaCIO, enamine derivatives, EDTA, and others [45 17]. Transport from the rectal epithelium primarily involves two routes, i.e., the paracellular route and the transcellular route. The paracellular transport mechanism implies that drugs diffuse through a space between epithelial cells. On the other hand, an uptake mechanism which depends on lipophilicity involves a typical transcellular transport route, and active transport for amino acids, carrier-mediated transport for (3-lactam antibiotics and dipeptides, and endocytosis are also involved in the transcellular transport system, but these transporters are unlikely to express in rectum (Figure 8.7). Table 8.3 summarizes the typical absorption enhancers in rectal routes. 

A lipophilic drug will preferably use the transcellular route since it will be easier for it to partition into the lipophilic cell membrane. The path length here is shorter than for the paracellular route but the drug has to move through several types of barriers (cell membrane, the cytoplasm, as well as intercellular spaces). Thus the equation for flux through the transcellular route is given as... 

Compounds that penetrate the stratum corneum via the transepidermal route may follow a transcellular (or intracellular) or intercellular pathway (see Figure 11.1). Because of the highly impermeable character of the cornified envelope (see previous section), the tortuous intercellular pathway has been suggested to be the route of preference for most drug molecules [32], This is confirmed by several microscopic transport studies, in which compounds have been visualized in the intercellular space of the stratum corneum [33-35]. Moreover, it has been demonstrated that drug permeation across stratum corneum increases many folds after lipid extraction [36], Hence, knowledge of the structure and physical properties of the intercellular lipids is crucial to broaden our insight into the skin barrier function. 

Almost all of the ophthalmic drugs that have been studied so far appear to cross the cornea by simple diffusion involving the paracellular and transcellular pathways (Figure 25.3). The paracellular pathway anatomically involves the intercellular space and is the primary route of... 

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). 

The second major obstacle of the oral delivery of proteins is the low permeability of proteins in the intestinal epithelium. The uptake of proteins is mediated by passive diffusion across the enterocytes (transcellular diffusion), paracellular diffusion (through intercellular spaces) and mostly by transcytosis (facilitated by receptor-mediated endocytosis). Erodible microcapsules and nanoparticles were shown to be absorbed intact through the GI tract and have opened the pos-... 

Studies using TEM and in situ precipitation to follow the pathway of topically applied compounds have focused on distinguishing between the intracellular and intercellular routes of transport of substances across the SC. In 1968, Silberberg [24] first used this technique to provide evidence that mercury, after topical application of 0.1% aqueous mercuric chloride, traverses across the SC in vitro via the intercellular spaces. But difficulties with fixation and processing prevented demonstration that the mercury aggregates were also present in the SC cells. Thus, the possibility that mercury may also have taken a transcellular route through the SC could not be excluded. 

Using isolated intact epithelial mucosal preparations, we have shown that, when lithium associated with the extracellular space was taken into account, acute cellular uptake of lithium was negligible (172). This is confirmed by experiments on lithium efflux from everted rings of rat jejunum (173). The recognition that intestinal uptake and transport of lithium may not involve transcellular transport of the metal agrees with proposed transport mechanisms for other alkali metals and magnesium (174). Metal-ion carrier proteins are not essential for rapid absorption of metals to occur their function is to assist when existing equilibrium conditions are unfavorable. 

Transcellular fluid Fluid in the gastrointestinal (GI) tract, cerebrospinal space, aqueous humor, pleural space, synovial space, and the peritoneal space ° Plasma fluid... 

For most topically applied drugs, passive diffusion along the concentration gradient, either transcellularly or paracellularly, is the main permeation mechanism across the cornea. Occasionally, a carrier-mediated active transport mechanism is indicated (Liaw et al. 1992). Lipophilic drugs tend to favour the transcellular route, whereas hydrophilic drugs usually permeate via the paracellular route through intercellular spaces (Borchardt 1990). 

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