Active transport parameters

Table 10.3 Activated transport parameters for earbon membrane...

Care should be exercised when attempting to interpret in vivo pharmacological data in terms of specific chemical—biological interactions for a series of asymmetric compounds, particularly when this interaction is the only parameter considered in the analysis (10). It is important to recognize that the observed difference in activity between optical antipodes is not simply a result of the association of the compound with an enzyme or receptor target. Enantiomers differ in absorption rates across membranes, especially where active transport mechanisms are involved (11). They bind with different affinities to plasma proteins (12) and undergo alternative metaboHc and detoxification processes (13). This ultimately leads to one enantiomer being more available to produce a therapeutic effect. 

In subsequent studies attempting to find a correlation of physicochemical properties and antimicrobial activity, other parameters have been employed, such as Hammett O values, electronic distribution calculated by molecular orbital methods, spectral characteristics, and hydrophobicity constants. No new insight on the role of physiochemical properties of the sulfonamides has resulted. Acid dissociation appears to play a predominant role, since it affects aqueous solubiUty, partition coefficient and transport across membranes, protein binding, tubular secretion, and reabsorption in the kidneys. An exhaustive discussion of these studies has been provided (10). 

No specific ionic selectivity is really admitted in pectins with monovalent counterions due to the relativity low charge parameter a very interesting behaviour is observed when divalent counterions are considered. Specially, it was demonstrated that when DM<50% the activity coefficient of magnesium is much larger than that of calcium. The transport parameters (f) were found following the order [45] ... 

In this book we will focus on physicochemical profiling in support of improved prediction methods for absorption, the A in ADME. Metabolism and other components of ADME will be beyond the scope of this book. Furthermore, we will focus on properties related to passive absorption, and not directly consider active transport mechanisms. The most important physicochemical parameters associated with passive absorption are acid-base character (which determines the charge state of a molecule in a solution of a particular pH), lipophilicity (which determines distribution of a molecule between the aqueous and the lipid environments), solubility (which limits the concentration that a dosage form of a molecule can present to the solution and the rate at which the molecule dissolves from... 

The published values for the activation energies and pre-exponential factors of transesterification and glycolysis vary significantly. Catalysts and stabilizers influence the overall reaction rate markedly, and investigations using different additives cannot be compared directly. Most investigations are affected by mass transport and without knowledge of the respective mass transport parameters, kinetic results cannot be transferred to other systems. 

The use of sterlo parameters such as and of methods such as the branching equations to represent sterlo effects on bio-activity Is Justified. Transport parameters are composite they are a function of differences In Intermolecular forces. The function of bulk and area parameters Is to provide the proper mix of Intennol-eoular forces required by a particular mode of bloaotlvlty. In the absence of parabolic or bilinear behavior bloactlv-Ity can be modeled by an equation based on Intermolecular forces and steric effects. 

Transport is a three-phase process, whereas homogeneous chemical and phase-transfer [2.87, 2.88] catalyses are single phase and two-phase respectively. Carrier design is the major feature of the organic chemistry of membrane transport since the carrier determines the nature of the substrate, the physico-chemical features (rate, selectivity) and the type of process (facilitated diffusion, coupling to gradients and flows of other species, active transport). Since they may in principle be modified at will, synthetic carriers offer the possibility to monitor the transport process via the structure of the ligand and to analyse the effect of various structural units on the thermodynamic and kinetic parameters that determine transport rates and selectivity. 

The rates of the forward ( f) and reverse (kT) reactions together with the mass transport parameters of the species involved in the transduction mechanism are important for the response of the sensor. Introducing reaction rates into the definition of the equilibrium constant introduces the notion of time. Thus, for the same value of K we can have fast and slow, forward and reverse reactions, and therefore fast or slow equilibrium. The equilibrium constant (K) is expressed in terms of activities. 

Fugate, H.N. 1989. Using total molecular surface area in quantitative structure activity relationships to estimate environmental fate and transport parameters. Master s thesis, Utah State University, Logan, UT. 

Two compounds had to be excluded from the data set. They were outliers (1.3 log units deviation) as also found in the analysis by Abraham et al. [26], It must also be remembered when considering the derived equations that log BB is a complex parameter that encompasses brain partitioning and permeability and may also depend on other processes such as metabolism, active transport, and so forth. Thus, the standard deviations of these determinations may fall within the range of the mean values. The authors could demonstrate that the derived equation could also estimate log BB outside of the training data set. Therefore, the value of the above correlation with the solvation free energy lies in its power to rank compounds for their ability to cross the blood-brain barrier before synthesis. Interestingly, it was also shown by Lombardo et al. [71] that the calculated AG°W correlated well with the determined permeability coefficient, PC, using endothelial cell monolayers from bovine brain mi-... 

When a saturable transporter is involved in the permeation process, the permeability is no longer a constant value but is dependent on the concentration of the substrate. In that case it is necessary to characterize the parameters of the carrier-mediated process, Km, the Michaelis-Menten constant related with the affinity by the substrate and Vmax, the maximal velocity of transport. If a passive diffusion process occurs simultaneously to the active transport pathway then it is necessary to evaluate the contribution of each transport mechanism. An example of how to characterize the parameters in two experimental systems and how to correlate them are described in the next section. 

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