Absorptive-mediated transcytosis

Certain proteins, such as insulin, transferrin, and insulin-like growth factors, cross the blood-brain barrier by receptor-mediated transcytosis. Once the protein binds to its membrane receptor, the membrane containing the receptor-protein complex is endocytosed into the endothelial cell to form a vesicle. It is released on the other side of the endothelial cell. Absorptive-mediated transcytosis also can occur. It differs from receptor-mediated transcytosis in that the protein binds nonspecifically to the membrane and not to a distinct receptor. 

RVG is a short peptide acting on neuronal cells and binds to the acetylcholine receptor. Chitosan acts as a cationic ligand and promotes the active transport of nano-conjugated systems. Here conjugated nanoparticles are delivered to the brain by two mechanisms absorptive-mediated transcytosis and receptor-mediated transcytosis. Biodistribution and efficient accumulation of p-galactosidase in the brain was analyzed in a mouse model (Fig. 10.10). The biodistribution results revealed that 3-galactosidase easily replaced disease-associated protein drugs. 

Kim KJ, Fandy TE, Lee VH, Ann DK, Borok Z, Crandall ED (2004) Net absorption of IgG via FcRn-mediated transcytosis across rat alveolar epithelial cell monolayers. Am J Physiol 287(3 ) L616-L622... 

Another method of delivery of insulin is to conjugate the protein with transferrin. Oral administration of the insulin-transferrin complex and insulin in streptozotocin-induced diabetic mice lowered the blood glucose levels by 28 and 5%, respectively. The blood glucose level was further decreased to 40% when the mice were pretreated with brefeldin A, a fungal metabolite, before the administration of the insulin-transferrin complex. The potentiation by brefeldin A indicated that insulin absorption could be accomplished through a transferrin receptor-mediated transcytosis in the intestinal wall. 

This refers to the transport across the epithelial cells, which can occur by passive diffusion, carrier-mediated transport, and/or endocytic processes (e.g., transcytosis). Traditionally, the transcellular route of nasal mucosa has been simply viewed as primarily crossing the lipoidal barrier, in which the absorption of a drug is determined by the magnitude of its partition coefficient and molecular size. However, several investigators have reported the lack of linear correlation between penetrant lipophilicity and permeability [9], which implies that cell membranes of nasal epithelium cannot be regarded as a simple lipoidal barrier. Recently, compounds whose transport could not be fully explained by passive simple diffusion have been investigated to test if they could be utilized as specific substrates for various transporters which have been identified in the... 

The nasal epithelium possesses selective absorption characteristics similar to those of a semipermeable membrane, i.e., it allows a rapid passage of some compounds while preventing the passage of others. The process of transportation across the nasal mucosa involves either passive diffusion, via paracellular or transcellular mechanisms, or occurs via active processes mediated by membrane-bound carriers or membrane-derived vesicles involving endo- or transcytosis. 

Figure 10.1 Pathways for intestinal absorption of macromolecular drugs, (a) Paracellular transport of macromolecules can be achieved by altering or disrupting the tight junctions that exist between cells and are only permeable to small molecules (<100 to 200 Da). (b) Adsorptive enterocytes and (c) M cells of Peyer s patches allow transcellular transport of macromolecules involving transcytosis and receptor-mediated endocytosis.

Fig. 3.1 Schematic presentation of absorption pathways through the intestinal epithelium. A passive transcellular B active, carrier-mediated C passive, paracellular D efflux transporters E transcytosis...

Three processes are involved in transcellular transport across the intestinal epithelial cells simple passive trans-port, passive diffusion together with an efflux pump, and active transport and endocytosis. Simple passive transport is the diffusion of molecules across the membrane by thermodynamic driving forces and does not require direct expenditure of metabolic energy. In contrast, active transport is the movement of molecules across the mem-brane resulting directly from the expenditure of metabolic energy and transport against a concentration gradient. Endocytosis processes include three mechanisms fluid-phase endocytosis (pinocytosis), receptor-mediated endocytosis, and transcytosis (Fig. 6). Endocytosis processes are covered in detail in section Absorption of Polypeptides and Proteins, later. 

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