Gradient-Dependent Transport Processes

Coupled transport systems frequently exhibit an asymmetric localization within plasma membranes. In enterocytes, the Na + -dependent glucose transporter and the a -dependent amino acid uptake systems are localized in apical (luminal) membrane, whereas the Na + / K+-ATPase is localized within the basolateral (blood-sided) membrane. Thus, the secondary active Na + - or H + -dependent transport systems are key elements for nutrient absorption, whereas subsequent transport across the basolateral membrane frequently follows the facilitated diffusion. 

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These examples draw the readers attention to the appearance of zero gradients in transport processes. Because these are confined to a specific location, they can serve, along with boimdary values of the dependent variable itself, as boundary conditions in the solution of the model equations. Thus the catalyst pellet shown in Figure 1.2a has two such conditions, one at the center, where the flux vanishes, and a second at the surface, where tiie reactant concentration attains a constant value. The pellet is encountered again in Chapter 4 (Illustration 4.9) where the xmderlying model is found to be a second-order differential equation. Such equations require the evaluation of two integration constants, and must therefore be provided with two boundary conditions. 

ATPase also catalyzed a passive Rb -Rb exchange, the rate of which was comparable to the rate of active Rb efflux. This suggested that the K-transporting step of H,K-ATPase is not severely limited by a K -occluded enzyme form, as was observed for Na,K-ATPase. Skrabanja et al. [164] also described the reconstitution of choleate solubilized H,K-ATPase into phosphatidylcholine-cholesterol liposomes. With the use of a pH electrode to measure the rate of H transport they observed not only an active transport, which is dependent on intravesicular K, but also a passive H exchange. This passive transport process, which exhibited a maximal rate of 5% of the active transport process, could be inhibited by vanadate and the specific inhibitor omeprazole, giving evidence that it is a function of gastric H,K-ATPase. The same authors demonstrated, by separation of non-incorporated H,K-ATPase from reconstituted H,K-ATPase on a sucrose gradient, that H,K-ATPase transports two protons and two ions per hydrolyzed ATP [112]. 

Anandamide is inactivated in two steps, first by transport inside the cell and subsequently by intracellular enzymatic hydrolysis. The transport of anandamide inside the cell is a carrier-mediated activity, having been shown to be a saturable, time- and temperature-dependent process that involves some protein with high affinity and specificity for anandamide (Beltramo, 1997). This transport process, unlike that of classical neurotransmitters, is Na+-independent and driven only by the concentration gradient of anandamide (Piomelli, 1998). Although the anandamide transporter protein has not been cloned yet, its well characterized activity is known to be inhibited by specific transporter inhibitors. Reuptake of 2-AG is probably mediated by the same facilitating mechanism (Di Marzo, 1999a,b Piomelli, 1999). 

Whereas other experimental methods have been used to obtain values of kti no other method provides values of k-t or equilibrium data. There are, however, several important limitations of our method. First, the method is restricted to relatively fast hole transport processes that can compete with charge recombination of the Sa -G+ radical ion pair (Fig. 6). This precludes the use of strong acceptors which can oxidize A as well as G (Fig. 2a). We find that hole transport cannot compete with charge recombination in such systems, even when a charge gradient is constructed which should favor hole transport [35]. Second, the method is unable to resolve the dynamics of systems in which return hole transport, k t, is very slow (<104 s-1) or systems in which multiple hole transport processes occur. Third, since the guanine cation radical cannot be detected by transient spectroscopy, the method is dependent upon the analysis of the behavior of Sa-. In section 3.4 we de-... 

For weak acids, e.g., salicylic acid, the dependency on a pH gradient becomes complex since both the passive diffusion and the active transport process will be dependent on the proton concentration in the apical solution [61, 63, 98, 105] and a lowering of the pH from 7.4 to 6.5 will increase the apical to basolateral transport more than 20-fold. Similarly, for weak bases such as alfentanil or cimetidine, a lowering of the pH to 6.5 will decrease the passive transport towards the basolateral side [105]. The transport of the ionizable compound will, due to the pH partition hypothesis, follow the pKa curve. 

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... 

It is clear that the achievement of equilibrium is assisted by the maximum contact between the reactant and the transporting gas, but the diffusion problem is complex, especially in a temperature gradient, when a process known as thermal diffusion occurs. The ordinary concentration-dependent diffusion process occurs across the direction of gas flow, but the thermal diffusion occurs along the direction of gas flow, and thus along the temperature gradient. 

The transport mechanisms that operate in distribution and elimination processes of drugs, drug-carrier conjugates and pro-drugs include convective transport (for example, by blood flow), passive diffusion, facilitated diffusion and active transport by carrier proteins, and, in the case of macromolecules, endocytosis. The kinetics of the particular transport processes depend on the mechanism involved. For example, convective transport is governed by fluid flow and passive diffusion is governed by the concentration gradient, whereas facilitated diffusion, active transport and endocytosis obey saturable MichaeUs-Menten kinetics. 

After a drug is absorbed, it is distributed into various tissue compartments. The rate at which this occurs is determined by the blood flow to the tissues as well as the rate of transfer of the drug from the blood into the tissues. This transfer depends on the vascular permeability to the drug, the relative binding of the drug to blood versus tissue components, the availability of active transport processes, and the concentration gradient... 

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