Transcellular absorption potential

For simple molecules, like p-adrenoceptor antagonists octanol/water log D74 values are remarkably predictive of absorption potential. Compounds with log Dy 4 values below 0 are absorbed predominantly by the paracellular route and compounds with log Dy 4 values above 0 are absorbed by the transcellular route. 

In a second approach, Sugano et al. [138] tried to consider paracellular transport in addition to transcellular permeation. The prediction of the paracellular transport potential was based on size and charge parameters together with artificial membrane permeability in relation to known human absorption values. Other groups have focused on the paracellular route by modification of the assay [26],... 

There are two routes potentially involved in drug absorption across the nasal epithelial barrier the transcellular and paracellular routes [20], Several experimental evidences dealing with the mechanism of transnasal permeation support the existence of both lipoidal pathyway (i.e., transcellular route) and an aqueous pore pathway (i.e., paracellular route). 

Poor intestinal absorption of a potential drug molecule can be related to poor physicochemical properties and/or poor membrane permeation. Poor membrane permeation could be due to low paracellular or transcellular permeability or the net result of efflux from transporter proteins including MDRl (P-gp) or MRP proteins situated in the intestinal membrane. Cell lines with only one single efflux transporter are currently engineered for in vitro permeability assays to get suitable data for reliable QSAR models. In addition, efforts to gain deeper insight into P-gp and ABC on a structural basis are going on [131, 132]. 

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. 

Cell culture models are routinely used to assess permeability of new potential drug candidates. The simplicity and higher throughput of these models makes them a useful alternative to in vivo studies. These models are used to predict absorption in vivo, rank order compounds and examine absorption mechanism. Transcellular, paracellular, active uptake and efflux mechanisms can be studied with these models. 

Physical barrier. Following oral administration of macromolecular drugs, their potential absorption pathways from the intestinal lumen to the bloodstream can be classified into transcellular transport associated with adsorptive or receptor-mediated endocytosis and paracellu-lar transport (Fig. 10.1). The GI tract surface consists of a tightly bound single layer of epithelial cells covered with thick and viscous mucus, which serves as a defensive deterrent against permeation of xenobi-otics and harmful pathogens. The epithelial cells in the GI tract are... 

The diffusant molecule from a topically applied formulation has three potential routes of entry to the subepidermal tissue (1) the transappenda-geal route, (2) the transcellular route and (3) the intercellular route (Fig. 2) [ ] Percutaneous absorption refers to the overall process of mass transport of substances applied topically and includes their transport across each layer of the skin and finally their uptake by the microcirculation of the skin. The process of percutaneous absorption can be described by a series of individual transport events occurring in sequence. First, deposition of a penetrant molecule onto the stratum corneum, then the diffusion through it and through the viable epidermis, the passage through the upper part of the papillary dermis, and finally uptake into the microcirculation for subsequent systemic distribution [1,3,4]. The viable tissue layers and the capillaries are relatively permeable, and the peripheral circulation is sufficiently rapid,... 

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