Endocytosis drug transport

After interaction of the aforementioned carriers with specific receptors, the carrier is then taken up by endocytosis and transported intracellularly to acidified endosomes and lyso-somes.The carrier is proteolytically degraded in the lysosomes and if a drug is coupled to the carrier, it is then released to diffuse into the cytoplasmic compartment. 

Simionescu N (1983) Cellular aspects of transcapillary exchange. Physiol Rev 63 1536-1579 Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387 569-572 Snoeck V, Goddeeris B, Cox E (2005) The role of enterocytes in the intestinal barrier function and antigen uptake. Microbes Infect 7 997-1004 Sugiyama Y, Kato Y (1994) Pharmacokinetic aspects of peptide delivery and targeting importance of receptor-mediated endocytosis. Drug Dev Ind Pharm 20 591-614 Takano M, Yumoto R, Murakami T (2006) Expression and function of efflux transporters in the intestine. Pharmacol Therap 109 137-161... 

Pinocytosis is a type of endocytosis that is responsible for the transport of large molecules such as proteins and colloids. Some cell types (e.g., endothelial cells) employ this transport mechanism extensively, but its importance in drug action is uncertain. 

Keywords Ocular drug delivery Noncorneal route Transporters Iontophoresis Endocytosis Dry eye Inflammation Subconjunctival injections... 

The transport mechanisms that operate in distribution and elimination processes of drugs, drug-carrier conjugates and pro-drugs include convective transport (for example, by blood flow), passive diffusion, facilitated diffusion and active transport by carrier proteins, and, in the case of macromolecules, endocytosis. The kinetics of the particular transport processes depend on the mechanism involved. For example, convective transport is governed by fluid flow and passive diffusion is governed by the concentration gradient, whereas facilitated diffusion, active transport and endocytosis obey saturable MichaeUs-Menten kinetics. 

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. 

Transcellular transport Basic mechanisms of transepithelial transport of drugs include passive transport of small molecules, active transport of ionic and polar compounds, and endocytosis and transcytosis of macromolecules. 

Drugs and other substances that pass through biologic membranes usually do so via passive diffusion, active transport, facilitated diffusion, or some special process such as endocytosis (Fig. 2-2). Each of these mechanisms is discussed here. 

Certain cells have the ability to transport substances across their membranes through processes such as endocytosis. Here the drug is engulfed by the cell via an invagination of the cell membrane. Although limited in scope, this method does allow certain large, nonlipid-soluble drugs to enter the cell. 

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... 

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.

Cells do have other transport options. Very small molecules can filter through the various channel proteins in the membrane. Drugs tend to be too large to pass by this method. The filtration of water is specifically called osmosis. Endocytosis is another method by which molecules may enter a cell. Endocytosis comes in many forms, all of which involve the indentation of a section of cell membrane that pinches off to form a new internal vesicle in the cell (Scheme 3.2). Once the cell breaks down the vesicle, the contents are released... 

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