Molecular interactions, transport

Second, P-gp differs from other transporters in that it recognizes its substrates when dissolved in the lipid membrane [52], and not when dissolved in aqueous solution. The site of recognition and binding has been shown to be located in the membrane leaflet facing the cytosol [53, 54], This implies that the membrane concentration of the substrate, Csm, determines activation [57]. Since the nature of a molecular interaction is strongly influenced by the solvent, the lipid membrane must be taken into account as the solvent for the SAR analysis of P-gp. Under certain conditions, the effect of additional solvents or excipients (used to apply hydrophobic substrates or inhibitors) on the lipid membrane and/or on the transporter must also be considered. Lipophilicity of substrates has long been known to play an important role in P-gp-substrate interactions nevertheless, the correlation of the octanol/water partition coefficients with the concentration of half-maximum... 

Self-consistent approaches in molecular modeling have to strike a balance of appropriate representation of the primary polymer chemistry, adequate treatment of molecular interactions, sufficient system size, and sufficient statistical sampling of structural configurations or elementary transport processes. They should account for nanoscale confinement and random network morphology and they should allow calculating thermodynamic properties and transport parameters. 

The most reliable method of obtaining the molecular interaction parameters is by fitting measured temperature-dependent transport data to the rigorous kinetic gas theory expressions, and extracting e and a. 

The previous section gave a simple treatment of transport properties based on the kinetic theory of gases. That approach has the advantages that it is very intuitive and mathematically tractable, and the final results are in approximate agreement with experiment and with more rigorous theory. To go beyond that treatment requires much more complex and specialized theory in statistical mechanics, molecular interactions and collisions [60,178, 269],... 

A model for sorption and transport of gases in polymers should serve two purposes. First, the model should convey an understanding of the molecular interactions which are responsible for the macroscopic processes, and second, the model should... 

Although less frequently compared with the reported cases of cytochrome P450 (CYP)-mediated dmg interactions, transporter-mediated dmg interactions have been reported in animals and humans. Unlike the CYP-mediated dmg interactions, which can be readily defined by inhibition or induction of CYP enzymes, the examples of transporter-mediated dmg interactions are often less conclusive (5-7). In many cases, transporter-mediated interactions are postulated on the basis of circumstantial evidence. Sometimes they are referred to as transporter-mediated dmg interactions because they cannot be explained by CYP inhibition or induction. Owing to the broad overlap in substrate specificity, many inhibitors and inducers can simultaneously affect both dmg transporters and CYP enzymes. Therefore, care should be exercised when exploring the underlying mechanisms of dmg interactions. The main purpose of this chapter is to explore the molecular mechanisms of dmg interactions involving dmg transporters. While the discussion will be focused predominantly on human data, examples from animal studies will also be used to assist in our understanding of the transporter-mediated dmg interactions. 

As noted above, as the size difference between the solvent and solute become progressively smaller, viscous flow rapidly becomes less important, and molecular interactions become dominant factors. In this limit, molecular solution (or sorption) and diffusion phenomena control the relative transport rates of the solute and solvent. This transition region is an area of ongoing discussion regarding what is a pore and what is not a pore ... 

Table 7.8 shows the thermal diffusion ratios and thermal diffusion coefficients obtained from Onsager s reciprocal rules for toluene, chlorobenzene, and bromobenzene at 1 atm and at 298 and 308 K. Thermal diffusion or heats of transport may be extremely sensitive to the molecular interactions in solutions (Rowley et al., 1988). 

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