Cell membranes diffusion/passive transport

Nutrients and waste products move through the cell membrane using passive transport (diffusion), facilitated transport, or active transport. 

Permeation of mAbs across the cells or tissues is accomplished by transcellular or paracellular transport, involving the processes of diffusion, convection, and cellular uptake. Due to their physico-chemical properties, the extent of passive diffusion of classical mAbs across cell membranes in transcellular transport is minimal. Convection as the transport of molecules within a fluid movement is the major means of paracellular passage. The driving forces of the moving fluid containing mAbs from (1) the blood to the interstitial space of tissue or (2) the interstitial space to the blood via the lymphatic system, are gradients in hydrostatic pressure and/or osmotic pressure. In addition, the size and nature of the paracellular pores determine the rate and extent of paracellular transport. The pores of the lymphatic system are larger than those in the vascular endothelium. Convection is also affected by tortuosity, which is a measure of hindrance posed to the diffusion process, and defined as the additional distance a molecule must travel in a particular human fluid (i. e., in vivo) compared to an aqueous solution (i. e., in vitro). 

In recent years, there has been increasing awareness regarding the importance of transporters in the absorption and disposition of NMEs. While the major portion of NMEs or marketed drugs traverse cell membranes by passive diffusion, there are numerous examples where the involvement of specialized transport mechanisms has been demonstrated. Examples include the role of oligopeptide transporters in the intestinal absorption of P-lactam antibiotics, angiotensinconverting enzyme (ACE) inhibitors, and novel NMEs as well as the role of P-glycoprotein (P-gp) in the secretion of molecules into the intestine [11,77—79]. Transfection of cells with the transporter protein of interest has permitted the evaluation of precise cellular mechanisms of uptake and transport of NMEs. Transfected cell lines by definition are tailor-made to overexpress the protein of... 

In summary, there appears to be evidence for both mechanisms of NH3/NH4 transport in bacterial cells. Passive difiFusion of NH3 would not generally lead to net accumulation by cells with an alkaline interior pH relative to the medium pH. Passive diffusion would be rate-limited by the low level of NH3 available at physiological pH and by the solubility properties of the cell membrane. NH4 active transport would be required for net ammonium uptake. However, net nitrogen accumulation could be accomplished by rapid assimilation of internal ammonia into amino acids. Net accumulation might be limited by the balance of the two processes uptake by active transport vs. loss by passive diffusion. 

It is often assumed that lipid molecules can readily traverse cell membranes by passive diffusion and freely access all cellular compartments without the need for any transport system. Despite its persistent popularity, this simplistic view is not likely to be correct. Strongly ionized lipids, such as phosphatidylcholine, are expected, of course, to require transport proteins because their charge would limit membrane diffusion. Indeed, ATP-dependent translocases that selectively extrude phospholipids from cells have... 

Substances move through cell membranes by diffusion (passive transport), facilitated transport, and active transport. 

Active Transport. Maintenance of the appropriate concentrations of K" and Na" in the intra- and extracellular fluids involves active transport, ie, a process requiring energy (53). Sodium ion in the extracellular fluid (0.136—0.145 AfNa" ) diffuses passively and continuously into the intracellular fluid (<0.01 M Na" ) and must be removed. This sodium ion is pumped from the intracellular to the extracellular fluid, while K" is pumped from the extracellular (ca 0.004 M K" ) to the intracellular fluid (ca 0.14 M K" ) (53—55). The energy for these processes is provided by hydrolysis of adenosine triphosphate (ATP) and requires the enzyme Na" -K" ATPase, a membrane-bound enzyme which is widely distributed in the body. In some cells, eg, brain and kidney, 60—70 wt % of the ATP is used to maintain the required Na" -K" distribution. 

AletabolicFunctions. The chlorides are essential in the homeostatic processes maintaining fluid volume, osmotic pressure, and acid—base equihbria (11). Most chloride is present in body fluids a Htde is in bone salts. Chloride is the principal anion accompanying Na" in the extracellular fluid. Less than 15 wt % of the CF is associated with K" in the intracellular fluid. Chloride passively and freely diffuses between intra- and extracellular fluids through the cell membrane. If chloride diffuses freely, but most CF remains in the extracellular fluid, it follows that there is some restriction on the diffusion of phosphate. As of this writing (ca 1994), the nature of this restriction has not been conclusively estabUshed. There may be a transport device (60), or cell membranes may not be very permeable to phosphate ions minimising the loss of HPO from intracellular fluid (61). 

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). 

Figure 1 General pathways through which molecules can actively or passively cross a monolayer of cells. (A) Endocytosis of solutes and fusion of the membrane vesicle with the opposite plasma membrane in an active process called transcytosis. (B) Similar to A, but the solute associates with the membrane via specific (e.g., receptor) or nonspecific (e.g., charge) interactions. (C) Passive diffusion between the cells through the paracellular space. (C, C") Passive diffusion (C ) through the cell membranes and cytoplasm or (C") via partitioning into and lateral diffusion within the cell membrane. (D) Active or carrier-mediated transport of an otherwise poorly membrane permeable solute into and/or out of a cellular barrier.

Models of lipid bilayers have been employed widely to investigate diffusion properties across membranes through assisted and non-assisted mechanisms. Simple monovalent ions, e.g., Na+, K+, and Cl, have been shown to play a crucial role in intercellular communication. In order to enter the cell, the ion must preliminarily permeate the membrane that acts as an impervious wall towards the cytoplasm. Passive transport of Na+ and Cl ions across membranes has been investigated using a model lipid bilayer that undergoes severe deformations upon translocation of the ions across the aqueous interface [126]. This process is accompanied by thinning defects in the membrane and the formation of water fingers that ensure appropriate hydration of the ion as it permeates the hydrophobic environment. 

Both active and passive transport occur simultaneously, and their quantitative roles differ at different concentration gradients. At low substrate concentrations, active transport plays a major role, whilst above the concentration of saturation passive diffusion is the major transport process. This very simple rule can be studied in an experimental system using cell culture-based models, and the concentration dependency of the transport of a compound as well as asymmetric transport over the membrane are two factors used to evaluate the presence and influence of transporters. Previous data have indicated that the permeability of actively absorbed compounds may be underestimated in the Caco-2 model due to a lack of (or low) expression of some uptake transporters. However, many data which show a lack of influence of transporters are usually derived from experiments... 

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