Passive diffusion/transport

Though drugs appear to cross the blood-brain barrier by passive diffusion, transporter systems in the blood-brain barrier pump drugs back out into the systemic circulation. As in the gut, the Pgp transporter system is the primary active transporter in the blood-brain barrier identified to date. This ATP-dependent transporter system picks up substrates that have crossed the capillary endothelial cells and transports them back to the systemic circulation, limiting their penetration into the CNS. Thus, not only are the physicochemical properties of the drug a determinant for penetration into the CNS but penetration also depends on whether the drug is a substrate for the Pgp transporter system. 

The term blood-brain barrier (BBB) refers to the special obstacle that drugs encounter when trying to enter the brain from the circulatory system. The difference between the brain and other tissues and organs is that the capillaries in the brain do not have pores for the free flow of small molecules in the interstitial fluid of the brain. To enter the interstitial fluid, all molecules must cross a membrane. This design is a protective measure to defend the brain from unwanted and potentially hazardous xenobiotics. Traditionally, drugs that target the brain or central nervous system (CNS) cross the BBB by passive diffusion. Transport by carrier proteins across the BBB is becoming better understood but remains an area of active research. 

The rate of passive diffusion transport across a membrane or cellular barrier is dependent on the concentration gradient as well as the characteristics of both the solute molecule and the barrier. The rate of... 

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). 

Porin channels are impHcated in the transport of cephalosporins because ceds deficient in porins are much more impermeable than are ceds that are rich in porins. The porins appear to function as a molecular sieve, adowing molecules of relatively low molecular weight to gain access to the periplasmic space by passive diffusion. In enterobacteria, a clear correlation exists between porin quantity and cephalosporin resistance, suggesting that the outer membrane is the sole barrier to permeabdity. However, such a relationship is not clearly defined for Pseudomonas aeruginosa where additional barriers may be involved (139,144,146). 

Various types of detector tubes have been devised. The NIOSH standard number S-311 employs a tube filled with 420—840 p.m (20/40 mesh) activated charcoal. A known volume of air is passed through the tube by either a handheld or vacuum pump. Carbon disulfide is used as the desorbing solvent and the solution is then analyzed by gc using a flame-ionization detector (88). Other adsorbents such as siUca gel and desorbents such as acetone have been employed. Passive (diffuse samplers) have also been developed. Passive samplers are useful for determining the time-weighted average (TWA) concentration of benzene vapor (89). Passive dosimeters allow permeation or diffusion-controlled mass transport across a membrane or adsorbent bed, ie, activated charcoal. The activated charcoal is removed, extracted with solvent, and analyzed by gc. Passive dosimeters with instant readout capabiUty have also been devised (85). 

Electrically assisted transdermal dmg deflvery, ie, electrotransport or iontophoresis, involves the three key transport processes of passive diffusion, electromigration, and electro osmosis. In passive diffusion, which plays a relatively small role in the transport of ionic compounds, the permeation rate of a compound is deterrnined by its diffusion coefficient and the concentration gradient. Electromigration is the transport of electrically charged ions in an electrical field, that is, the movement of anions and cations toward the anode and cathode, respectively. Electro osmosis is the volume flow of solvent through an electrically charged membrane or tissue in the presence of an appHed electrical field. As the solvent moves, it carries dissolved solutes. 

From a thermodynamic and kinetic perspective, there are only three types of membrane transport processes passive diffusion, faeilitated diffusion, and active transport. To be thoroughly appreciated, membrane transport phenomena must be considered in terms of thermodynamics. Some of the important kinetic considerations also will be discussed. 

Passive diffusion is the simplest transport process. In passive diffusion, the transported species moves across the membrane in the thermodynamically favored direction without the help of any specific transport system/molecule. For an uncharged molecule, passive diffusion is an entropic process, in which movement of molecules across the membrane proceeds until the concentration of the substance on both sides of the membrane is the same. For an uncharged molecule, the free energy difference between side 1 and side 2 of a membrane (Figure 10.1) is given by... 

Does this transport operate by passive diffusion or by facilitated diffusion ... 

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. 

It is possible that the stationary-state situations leading to an active ion transport occur only in localized regions of the membrane, i.e., at ATPase molecule units with diameters of about 50 A and a length of 80 A. The vectorial ion currents at locations with a mixed potential and special equipotential lines would appear phenomenologically like ionic channels. If the membrane area where the passive diffusion occurs is large, it may determine the rest potential of the whole cell. 

By far the most complete study of the kinetics of mammalian passive glucose transporters has been done on the GLUT-1 isoform in the human erythrocyte. The transport of glucose in this cell type is a classic example of facilitated diffusion, the... 

Thus, the ideas above do not suffice for an interpretation of all experimental results. These ideas include the assumption that the ions move in the membrane only under the effect of concentration and potential gradients (diffusion and migration), and that transport of one sort of ions is independent of the transport of other sorts of ions. This transport of ions under the effect of external forces has been named passive ionic transport. 

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-... 

Eischer, H. Passive diffusion and active transport through biological membranes - binding of drugs to... 

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. 

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. 

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