Transport mechanisms passive diffusion

In order to design such an efficient and effective device, one must understand the mechanisms by which drug is transported in the ocular interior. One issue debated in the literature for some time has been the relative importance of transport by passive diffusion versus that facilitated by the flow of fluid in the vitreous (see, e.g., Ref. 226). To predict the geometric distribution even at steady state of drug released from an implant or an intravitreal injection, one must appreciate which of these mechanisms is at work or, as appropriate, their relative balance. 

More simply, in the early regions of the tubule (proximal tubule and Loop of Henle), Na+ ions leave the lumen and enter the tubular epithelial cells by way of passive facilitated transport mechanisms. The diffusion of Na+ ions is coupled with organic molecules or with other ions that electrically balance the flux of these positively charged ions. In the latter regions of the tubule (distal tubule and collecting duct), Na+ ions diffuse into the epithelial cells through Na+ channels. 

Several mechanisms for the transport of ions are operative (1) active transport of the ion against a concentration gradient by an ATP-driven membrane carrier, (2) passive carrier facilitated transport, (3) passive diffusion dependent upon the abihfy of the ion or complex to pass the membrane. Sodium,... 

In contrast to active transport, passive transport as a whole does not involve energy consumption and, therefore, only can work down a concentration gradient (or other types of gradients, such as electrochemical potential, thermal, or pressure gradients). In other words, passive transport of molecules equalizes their chemical potential on both sides of the membrane. The process of passive transport can be subdivided into two different mechanisms passive diffusion and facilitated transport. Passive diffusion is a physico-chemical process, whereas in facilitated transport, molecules pass through the membrane via special channels or are translocated via carrier proteins. Both passive diffusion and facilitated transport, in contrast to active transport, follow a gradient, where facilitation merely lowers the activation energy for the transport process. 

The simplest form of molecular transport is passive diffusion. The driving force for passive diffusion is a concentration gradient. That is, a chemical in solution will move from an area of relatively high concentration to a region of lower concentration. Passive diffusion is the primary transport mechanism in many areas of the body where molecules must cross a membrane (outer surface of cell) or cellular barrier (layer of cells, such as in the capillary wall or intestinal wall) without the aid of specialized transporter proteins or fluid movement. 

Transcellular transport mechanisms are responsible for the transport of free amino acids through epithelial cells and are mainly present in cells of the intestinal mucosa and the renal tubules. Most amino acids are transported via a sodium-dependent transport system. However, sodium-independent transport and passive diffusion exist. Transmembrane transporters may be specific for single amino acids (e.g. histidine, glycine) or for groups of amino acids (e.g. dibasic amino acids, dibasic amino acids and cystine, neutral amino acids or dicarboxylic amino acids). 

In the simplest transport mechanism called diffusion or passive transport, molecules can diffuse from a higher concentration to a lower concentration. For example, small molecules such as O2, CO2, urea, and water diffuse via passive transport through cell membranes. If their concentrations are greater outside the cell than inside, they diffuse into the cell. If their concentrations are higher within the cell, they diffuse out of the cell. 

The ability of doxombicin formulated with the copolymer to avoid accumulation in acidic cytoplasmic vesicles is probably the most important contributor to its mechanism of action. Resistance-modulating agents and some polymer conjugates can partially reduce the dmg resistance mediated by ATP-dependent transporters by either directly inhibiting these transporters , or by switehing the dmg transport from passive diffusion to endocytosis. At the same time, they cannot overcome the endosomal barrier that represents the seeond level of resistance in drug resistant cells. The fact that Pluronic L61/doxombicin can effectively penetrate the plasma membrane of resistant cells and, at the same time, avoid sequestration in the vesicles suggests that this product may be more clinically effective than other doxombicin-based products. 

Materials may be absorbed by a variety of mechanisms. Depending on the nature of the material and the site of absorption, there may be passive diffusion, filtration processes, faciHtated diffusion, active transport and the formation of microvesicles for the cell membrane (pinocytosis) (61). EoUowing absorption, materials are transported in the circulation either free or bound to constituents such as plasma proteins or blood cells. The degree of binding of the absorbed material may influence the availabiHty of the material to tissue, or limit its elimination from the body (excretion). After passing from plasma to tissues, materials may have a variety of effects and fates, including no effect on the tissue, production of injury, biochemical conversion (metaboli2ed or biotransformed), or excretion (eg, from liver and kidney). 

The thylakoid membrane is asymmetrically organized, or sided, like the mitochondrial membrane. It also shares the property of being a barrier to the passive diffusion of H ions. Photosynthetic electron transport thus establishes an electrochemical gradient, or proton-motive force, across the thylakoid membrane with the interior, or lumen, side accumulating H ions relative to the stroma of the chloroplast. Like oxidative phosphorylation, the mechanism of photophosphorylation is chemiosmotic. 

Poorly absorbed compounds have been identified as those with a PSA>140Af Considering more compounds, considerable more scatter was found around the sigmoidal curve observed for a smaller set of compounds [74]. This is partly due to the fact that many compounds do not show simple passive diffusion only, but are affected by active carriers, efflux mechanisms involving P-glycoprotein (P-gp) and other transporter proteins, and gut wall metabohsm. These factors also con-... 

FIG. 2 Mechanisms of drug transfer in the cellular layers that line different compartments in the body. These mechanisms regulate drug absorption, distribution, and elimination. The figure illustrates these mechanisms in the intestinal wall. (1) Passive transcellular diffusion across the lipid bilayers, (2) paracellular passive diffusion, (3) efflux by P-glycoprotein, (4) metabolism during drug absorption, (5) active transport, and (6) transcytosis [251]. 

Substances pass through membranes primarily by passive diffusion. In addition, in biological membranes, substances may penetrate through specific transport mechanisms. 

Two principal routes of passive diffusion are recognized transcellular (la —> lb —> lc in Fig. 2.7) and paracellular (2a > 2b > 2c). Lateral exchange of phospholipid components of the inner leaflet of the epithelial bilayer seems possible, mixing simple lipids between the apical and basolateral side. However, whether the membrane lipids in the outer leaflet can diffuse across the tight junction is a point of controversy, and there may be some evidence in favor of it (for some lipids) [63]. In this book, a third passive mechanism, based on lateral diffusion of drug molecules in the outer leaflet of the bilayer (3a > 3b > 3c), wih be hypothesized as a possible mode of transport for polar or charged amphiphilic molecules. 

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