Membrane transport carrier-mediated

This mechanism is important for compounds that lack sufficient lipid solubility to move rapidly across the membrane by simple diffusion. A membrane-associated protein is usually involved, specificity, competitive inhibition, and the saturation phenomenon and their kinetics are best described by Michaelis-Menton enzyme kinetic models. Membrane penetration by this mechanism is more rapid than simple diffusion and, in the case of active transport, may proceed beyond the point where concentrations are equal on both 

Passive facilitated diffusion involves movement down a concentration gradient without an input of energy. This mechanism, which may be highly selective for specific conformational structures, is necessary for transport of endogenous compounds whose rate of transport by simple diffusion would otherwise be too slow. The classical example of facilitated diffusion is transport of glucose into red blood cells. 

There are instances in which toxicants have chemical or structural similarities to endogenous chemicals that rely on these special transport mechanisms for normal physiological uptake and can thus utilize the same system for membrane transport. Useful examples of drugs known to be transported by this mechanism include levodopa, which is used in treating Parkinson s disease, and fluorouracil, a cytotoxic drug. Levodopa is taken up by the carrier that normally transports phenylalanine, and fluorouracil is transported by the system that carries the natural pyrimidines, thymine, and uracil. Iron is absorbed by a specific carrier in the mucosal cells of the jejunum, and calcium by a vitamin D-dependent carrier system. Lead may be more quickly moved by a transport system that is normally involved in the uptake of calcium. 

For carrier-mediated transport, the rate of movement across a membrane will now be constant, since flux is dependent on the capacity of the membrane carriers and not the mass of the chemical to be transported. These processes are described by zero-order kinetic rate equations of the form  

K0 is now the zero-order rate constant and is expressed in terms of mass/time. In an active carrier-mediated transport process following zero-order kinetics, the rate of drug transport is always equal to K once the system is fully loaded or saturated. At subsaturation levels, the rate is initially first order as the carriers become loaded with the toxicant, but at concentrations normally encountered in pharmacokinetics, the rate becomes constant. Thus, as dose increases, the rate of transport does not increase in proportion to dose as it does with the fractional rate constant seen in first-order process. This is illustrated in the Table 6.1 where it is assumed that the first-order rate constant is 0.1 (10% per minute) and the zero-order rate is 10 mg/min. 

---

SlROTNAK, F. M. AND B. TOLNER. Carrier-mediated membrane transport of folates in mammalian cells. Annu. Rev. Nutr. 1999, 39, 91-122. 

Carrier-mediated membrane transport proteins on the RPE selectively transport nutrients, metabolites, and xenobiotics between the choriocapillaris and the cells of the distal retina, and include amino acid [33 35], peptide [36], dicarboxylate, glucose [37], monocarboxylic acid [38,39], nucleoside[40], and organic anion and organic cation [41] transporters. Membrane barriers such as the efflux pumps, including multidrug resistance protein (P-gp), and multidrug resistance-associated protein (MRP) pumps have also been identified on the RPE. Exploitation of these transport systems may be the key to circumventing the outer BRB. 

In facilitated transport (also known as carrier-mediated membrane transport), a substance combines with a specific carrier protein on the membrane, and the resultant protein-sub-stance complex diffuses to the other side of the membrane, where it dissociates to release the substance. The absorption of glucose from the intestines into the blood, for example, requires facilitated transport of glucose across the cellular membranes of the epitheleal lining of the intestines. Many amino adds cross cellular membranes by fadlitated transport. 

Figure 9.5 Kinetics of a carrier-mediated membrane transport processes and passive diffusion. At passive diffusion, the transport...

Gallagher, P. M. Athayde, A. L. Ivory, C. F. "Electrochemical Coupling in Carrier-Mediated Membrane Transport" /. Membrane Sri., 1986a, 29 p.49. 

Fig. 9 Schematic representation depicting the movement of molecules from the absorbing (mucosal or apical) surface of the GIT to the basolateral membrane and from there to blood. (A) transcellular movement through the epithelial cell. (B) Paracellular transport via movement between epithelial cells. (Q Specialized carrier-mediated transport into the epithelial cell. (D) Carrier-mediated efflux transport of drug out of the epithelial cell. (Copyright 2000 Saguaro Technical Press, Inc., used with permission.)...

The transport of amino acids at the BBB differs depending on their chemical class and the dual function of some amino acids as nutrients and neurotransmitters. Essential large neutral amino acids are shuttled into the brain by facilitated transport via the large neutral amino acid transporter (LAT) system [29] and display rapid equilibration between plasma and brain concentrations on a minute time scale. The LAT-system at the BBB shows a much lower Km for its substrates compared to the analogous L-system of peripheral tissues and its mRNA is highly expressed in brain endothelial cells (100-fold abundance compared to other tissues). Cationic amino acids are taken up into the brain by a different facilitative transporter, designated as the y system, which is present on the luminal and abluminal endothelial membrane. In contrast, active Na -dependent transporters for small neutral amino acids (A-system ASC-system) and cationic amino acids (B° system), appear to be confined to the abluminal surface and may be involved in removal of amino acids from brain extracellular fluid [30]. Carrier-mediated BBB transport includes monocarboxylic acids (pyruvate), amines (choline), nucleosides (adenosine), purine bases (adenine), panthotenate, thiamine, and thyroid hormones (T3), with a representative substrate given in parentheses [31]. 

A superficial examination of experimental results obtained by using labeling techniques (electrodialytic transport through solvent polymeric membranes) indicates that there might be a substantial transport of water coupled with the carrier-mediated ion transport. This would be rather surprising because the cation in the carrier-cation complex is not hydrated. 

The carrier-mediated active transport system of calcium is responsible for the relaxation of muscle. However, the rate of efflux from sarcoplasmic reticulum membranes during reversal of the transport process is 102 to 104 orders too low to account for the massive calcium release from sarcoplasmic reticulum in stimulated muscle. Instead, passive diffusion of calcium across the sarcoplasmic reticulum membrane will proceed during excitation of muscle178,179,186. The rate of calcium release observed during excitation is 1.000-3.000 p moles/mg protein/min which is an increase of about 104 to 10s over the resting state. 

Chloroplasts are enclosed by two membranes. The outer membrane is freely permeable to small molecules (up to about 10 kDa) due to the presence of a porin and the inner membrane is the osmotic barrier and the site where specific transport occurs. The specificity of envelope permeability is strikingly highlighted by the contrast between Pi and PP the former being among the most rapidly translocated molecules and the latter among those to which the envelope is relatively impermeable. Carrier-mediated anion transport can be classified as ... 

Figure 3. Schematic diagram of an apparatus for measuring transmembrane oxidation-reduction in a planar bilayer membrane. The mechanism described is simple carrier-mediated electron transport. D = aqueous electron donor A = aqueous electron acceptor ...

Carrier-Mediated Intestinal Transport. Various carrier mediated systems (transporters) are present at the intestinal brush border and basolateral membrane for theabsorption of specific ions and nutrients essential for the body. Many drugs are absorbed by these carriers because of the structural similarity to natural substrates. An intestinal transmembrane protein, P-Glycoprotein (F-Gp) appears to reduce apparent intestinal epithelial cell permeability from lumen to... 

Carrier-mediated intestinal transport Various carrier mediated systems (transporters) are present at the intestinal brush border and basolateral membrane for... 

One of the most important categories of ion selective chemical sensors is based on what are called liquid membranes. This term was flrst used in 196U to describe a matrix that is not water soluble it contains either anionic or cationic sites (liquid ion exchangers), which can selectivity facilitate the exchange of inorganic ions. In order to study the active carrier-mediated ion transport through these liquid membranes, a cell such as the one shown in Figure 3.4.4 has been employed. 

It is not uncommon for drug compounds to be able to perform very well in a variety of microtiter plate-based assays, but when transferred to in vivo assays, they cannot reach the therapeutic target site. The molecule must permeate through a number of cell membranes made up of phospholipid bilayers, which can increase the passage of highly charged polar molecules. Among the most common means by which a molecule can cross such a membrane are transcellular routes such as passive diffusion, carrier-mediated active transport, and metabolic enzymes, paracellular... 

Apart from ammonia, some other inorganic species extracted by hquid membranes are strong acids like nitric acid and thiocyanate ions from aqueous solutions using carrier-mediated coupled transport process. 

Carrier Mediated Ion Transport through Artificial and Biological Membranes... 

The kinetics of carrier-mediated cation transport through bilayer membranes have also been investigated. Figure 18 shows a scheme of four different processes,... 

Fig. 18. Mechanism of carrier-mediated ion transport through a lipid bilayer membrane [Reproduced from Stark, G., et.al Biophys. j. 11, 981 (1971) and Benz, R., Stark, G. Biochem. Biophys. Acta 382 (1), 27 (1975).]...

Nonequilibrium noise generated by carrier-mediated ion transport was studied in lipid bilayers modified by tetranactin (41). As expected, deviations of measured spectral density from the values calculated from the Nyquist formula 1 were found. The instantaneous membrane current was described as the superposition of a steady-state current and a fluctuating current, and for the complex admittance in the Nyquist formula only a small-signal part of the total admittance was taken. The justification of this procedure is occasionally discussed in the literature (see, for example, Tyagai (42) and references cited therein), but is unclear. 

Uptake of alkaloids by isolated vacuoles and transport mechanisms over membranes have been studied in detail. Carrier-mediated active transport... 

---