Transcellular pathway

Based on the majority of observations of particulate uptake in the intestine, transcellular transport, specifically through the epithelium of the Peyer s patch, appears to be the primary pathway of microparticulate absorption (LeFevre and Joel, 1984 Pappo eta/., 1991 Eldridge eta/., 1990 Damge et a/., 1990 Pappo and Erma 1989). Furthermore, most of the transcellular transport involves M cells (Bockman and Cooper, 1973 Joel eta/., 1978, 1970 LeFevre eta/., 1978a), though there have been a few select instances in which other cell types appeared to be involved (Wells et a/., 1988 Landsverk, 1988). 

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Two distinguishing features of gastrointestinal active and facilitated transport processes are that they are capacity-limited and inhibitable. Passive transcellular solute flux is proportional to mucosal solute concentration (C), where the proportionality constant is the ratio of the product of membrane diffusion coefficient (Dm) and distribution coefficient (Kd) to the length of the transcellular pathway (Lm). 

While both paracellular and passive transcellular pathways are available to a solute, the relative contribution of each to the observed transport will depend on the properties of the solute and the membrane in question. Generally, polar membrane-impermeant molecules diffuse through the paracellular route, which is dominated by tight junctions (Section III.A). Exceptions include molecules that are actively transported across one or both membrane domains of a polarized cell (Fig. 2). The tight junction provides a rate-limiting barrier for many ions, small molecules, and macromolecules depending on the shape, size, and charge of the solute and the selectivity and dimensions of the pathway. 

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. 

Transport of the compound AZ001 and markers for paracellular and transcellular pathways in the presence and absence of EDTA... 

Molecules with a large molecular weight or size are confined to the transcellular route and its requirements related to the hydrophobicity of the molecule. The transcellular pathway has been evaluated for many years and is thought to be the main route of absorption of many drugs, both with respect to carrier-mediated transport and passive diffusion. The most well-known requirement for the passive part of this route is hydrophobicity, and a relationship between permeability coefficients across cell monolayers such as the Caco-2 versus log P and log D 7.4 or 6.5 have been established [102, 117]. However, this relationship appears to be nonlinear and reaches a plateau at around log P of 2, while higher lipophilicities result in reduced permeability [102, 117, 118]. Because of this, much more attention has recently been paid towards molecular descriptors other than lipophilicity [86, 119-125] (see section 5.5.6.). The relative contribution between the para-cellular and transcellular components has also been evaluated using Caco-2 cells, and for a variety of compounds with different charges [110, 112] and sizes [112] (see Section 5.4.5). 

The oral administration of large proteins and peptides is limited due to their low membrane permeability. These compounds are mainly restricted to the para-cellular pathway, but because of their polar characteristics and their size the pore of the tight junctional system is also highly restrictive. An additional transcellular pathway has therefore been suggested for these peptides, i.e., the transcytotic pathway, which involves a receptor-mediated endocytosis in Caco-2 cells [126],... 

There are two pathways by which a drug molecule can cross the epithelial cell the transcellular pathway, which requires the drug to permeate the cell membranes, and the paracellular pathway, in which diffusion occurs through water-filled pores of the tight junctions between the cells. Both the passive and the active transport processes may contribute to the permeability of drugs via the transcellular pathway. These transport pathways are distinctly different, and the molecular properties that influence drug transport by these routes are also different (Fig. 

Under normal conditions, the transcellular route is not considered as the preferred way of dermal invasion, the reason being the very low permeability through the corneocytes and the obligation to partition several times from the more hydrophilic corneocytes into the lipid intercellular layers in the stratum corneum and vice versa. The transcellular pathway can gain in importance when a penetration enhancer is used, for example, urea, which increases the permeability of the corneocytes by altering the keratin structure. 

Keywords Colon Controlled release Sustained release Rat Single-pass perfusion Recirculation Closed loop Carrier-mediated transport Passive transport Membrane permeability P-glycoprotein Paracellular pathway Transcellular pathway... 

Only predictive for transcellular pathway Low predictive value... 

Passive Transcellular Pathway pH Partition Theory as the Basis of Understanding Membrane Permeability... 

Intestinal absorption of Ca is via two distinct mechanistic routes which involve the (i) transcellular pathway, a saturable active transfer process that is unidirectional (i.e., mucosal-to-serosal), and (ii) the paracellular... 

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... 

The transcellular pathway has been discredited as a major pathway, although some polar substances can penetrate the outer surface of the protein filaments of hydrated stratum comeum. The transfollicularpathway is really an invagination of the epidermis into the dermis, and the chemical still has to penetrate the epidermis to be absorbed into the blood stream. This is also a regarded as minor route. Sweat pores are not lined with the stratum comeum layer, but the holes are small, and this route is still considered a minor route for chemical absorption. In general, the epidermal surface is 100 to 1000 times the surface area of skin appendages, and it is likely that only very small and/or polar molecules penetrate the skin via these appendages. 

The transcellular pathway involves the movement of the drag across the epithelial cell, by active and/or passive processes (Figure 1.3), which are discussed in detail below. 

The surface area of brush border membranes is 1000 fold larger than paracellular surface area (Pap-penheimer and Reiss 1987). Therefore, the probability for transcellular permeability is much higher than for paracellular permeability. Indeed, lipophilic drugs with rapid and complete absorption have a high probability for passive transcellular route. Hydrophilic drags tend to pass cellular membranes via water filled pores in the paracellular pathway (for review, see Lee et al. 1991). However, there is also a part of hydrophilic molecules passing membranes by transcellular route (Nellans 1991). The paracellular pathway is used by some positively charged compounds whereas transcellular pathway is preferred with unionised compounds. 

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