Passive diffusion—

Passive diffusion. Diffusion occurs through the lipid membrane. 

Filtration. Diffusion occurs through aqueous pores. 

Special transport. Transport is aided by a carrier molecule, which act as a ferryboat.  

Endocytosis. Transport takes the form of pinocytosis for liquids and phagocytosis for solids. 

The first and third routes are important in relation to pharmacokinetic mechanisms. The aqueous pores are too small in diameter for diffusion of most drugs and toxicant, although important for movement of water and small polar molecules (e.g., urea). Pinocytosis is important for some macromolecules (e.g., insulin crossing the blood-brain barrier). 

FIGURE 14.2 Molecular dynamics simulation of the diffusion of benzene within a hydrated lipid bilayer membrane. Benzene molecules are shown as Corey-Pauling-Koltun (CPK) models atoms in the phospholipid head groups are shown as ball and stick models and hydrocarbon chains and water molecules as dark and light stick models, respectively. (Reproduced with permission from Bassolino-Klinaas D, Alper HE, Stouch TR. Biochemistry 1993 32 12624-37.) 

Extensive efforts have been made to develop quantitative structure/activity relationships (QSARs) that predict membrane transport (16, 17). Particularly extensive use has been made of log P (log solvent/water partition coefficient values) and the Hansch equation (Equation 14.3)  

Drug class System correlated with activity  

Adapted from Table VI in Austel B, Kutter R. Absorption, distribution and metabolism of drugs. In Toplis JG, ed. Quantitative structure activity relationships. Medicinal chemistry monographs, vol 19. New York Academic Press 1983. p. 437—96. 

Apart from these basic rules of thumb, the ability to predict the relationship between molecular structure and transport across biological membranes is limited beyond narrow ranges of known compounds. Confounding factors include inaccurate, incomplete, and/or noncomparable data, and the potential existence of multiple drug transport mechanisms in real biological membranes. In particular, limited QSAR data are available for the specific drug transporters that are considered in the following sections. 

Substances can be transported across epithelial membranes by simple passive diffusion, carrier-mediated diffusion, and active transport, in addition to other specialized mechanisms, including endocytosis. 

There has also been a report regarding the active transport of antibacterial agents in oral mucosa. In a cell line derived from oral epithelium, the uptake of ciprofloxacin and minocycline was not only saturable and inhibited in the presence of other compounds, but the intracellular levels of both antibiotics were 8 10-fold higher than the extracellular levels as well, demonstrating an active transport process [18]. Whether the permeability of these compounds across the entire oral mucosa occurs via an active transport process, however, remains to be determined. 

Transfer across membranes occurs down a concentration gradient (i.e. from regions of high drug concentration to regions where the concentration is lower). The process of diffusion can be described by Fick s law (named after the German physiologist, Adolf Fick), which states 

At equilibrium there is a zero free-energy change, AG=0, that takes place between compartments separated by a membrane, with the free-energy change being dependent on the difference in concentration of various ions and the electrical potential difference that exists across the membrane. The relationships among sodium, potassium, and chloride ions, pH, and electrolytic potential have become known as Donnan equilibria. The concentrations and electrolytic potentials are related by the following equation  

If going down the concentration gradient—C2 is less than Ci—the first term in equation 5.3 will be negative (remember AG = -i Tln Ae,), and if going up the concentration gradient—Q is less than C2—the first term will be positive. 

TABLE 5.2 Concentration of Some Ions in Living CeUs (mM) 

This calculation ignores the effect of the proton (pH) and other ions that may be present—mainly sodium ion since the concentrations of calcium and magnesium ions usually are much lower (see Table 5.2). 

Increasing lipophilicity can, however, result in a decrease in solubility, which, in turn, can result in solubility/dissolution problems and ultimately adversely affect intestinal absorption (Oh, 1991). 

Besides diffusion across the lipid bilayer of intestinal epithelial cells, another mechanism by which peptides and proteins can be absorbed is by diffusion through aqueous pores in the cell membrane. Aqueous pore diffusion in undamaged cells, though, is probably dominated by smaller-molecular-weight species, particularly those that are water-soluble and are not taken up by carrier-mediated transport mechanisms (Pusztai, 1989). 

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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. 

Aquatic organisms, such as fish and invertebrates, can excrete compounds via passive diffusion across membranes into the surrounding medium and so have a much reduced need for specialised pathways for steroid excretion. It may be that this lack of selective pressure, together with prey-predator co-evolution, has resulted in restricted biotransformation ability within these animals and their associated predators. The resultant limitations in metabolic and excretory competence makes it more likely that they will bioacciimiilate EDs, and hence they may be at greater risk of adverse effects following exposure to such chemicals. 

Passive diffusion sorbent badges are useful for screening and monitoring certain chemical exposures, especially vapors and gases. 

Chemicals have to pass through either the skin or mucous membranes lining the respiratory airways and gastrointestinal tract to enter the circulation and reach their site of action. This process is called absorption. Different mechanisms of entry into the body also greatly affect the absorption of a compound. Passive diffusion is the most important transfer mechanism. According to Pick s law, diffusion velocity v depends on the diffusion constant (D), the surface area of the membrane (A), concentration difference across the membrane (Ac), and thickness of the membrane (L)... 

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... 

FIGURE 10.1 Passive diffusion of an uncharged species across a membrane depends only on the concentrations (Q and Cg) on the two sides of the membrane. 

FIGURE 10.2 The passive diffusion of a charged species across a membrane depends upon the concentration and also on the charge of the particle, Z, and the electrical potential difference across the membrane, Ai/<. 

FIGURE 10.3 Passive diffusion and facilitated diffusion may be distinguished graphically. The plots for facilitated diffusion are similar to plots of enzyme-catalyzed processes (Chapter 14) and they display saturation behav-... 

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. 

Fig. 5. Tentative mixed potential model for the sodium-potassium pump in biological membranes the vertical lines symbolyze the surface of the ATP-ase and at the same time the ordinate of the virtual current-voltage curves on either side resulting in different Evans-diagrams. The scale of the absolute potential difference between the ATP-ase and the solution phase is indicated in the upper left comer of the figure. On each side of the enzyme a mixed potential (= circle) between Na+, K+ and also other ions (i.e. Ca2+ ) is established, resulting in a transmembrane potential of around — 60 mV. This number is not essential it is also possible that this value is established by a passive diffusion of mainly K+-ions out of the cell at a different location. This would mean that the electric field across the cell-membranes is not uniformly distributed.

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. 

Uptake of LCFAs across the lipid-bilayer of most mammalian cells occurs through both a passive diffusion of LCFAs and a protein-mediated LCFA uptake mechanism. At physiological LCFA concentrations (7.5 nM) the protein-mediated, saturable, substrate-specific, and hormonally regulated mechanism of fatty acids accounts for the majority (>90%) of fatty acid uptake by tissues with high LCFA metabolism and storage such as skeletal muscle, adipose tissue, liver,... 

The outer membrane of gram-negative bacteria is a permeability barrier that allows the passive diffusion of small hydrophilic antibiotics only through aqueous channels, the porins. Drugs larger than 800 Da are... 

Due to their physicochemical properties trace amines can pass the cell membrane to a limited extent by passive diffusion, with the more lipophilic PEA and TRP crossing membranes more readily than the more polar amines TYR. and OCT. In spite of these features, trace amines show a heterogeneous tissue distribution in the vertebrate brain, and for TYR. and OCT storage in synaptic vesicles as well as activity-dependent release have been demonstrated. So far, trace amines have always been found co-localized with monoamine neurotransmitters, and there is no evidence for neurons or synapses exclusively containing trace amines. 

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