Partition coefficient membrane systems

Some specific solutes diffuse down electrochemical gradients across membranes more rapidly than might be expected from their size, charge, or partition coefficients. This facilitated diffusion exhibits properties distinct from those of simple diffusion. The rate of facilitated diffusion, a uniport system, can be saturated ie, the number of sites involved in diffusion of the specific solutes appears finite. Many facihtated diffusion systems are stereospecific but, fike simple diffusion, require no metabolic energy. 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

A CRO may also allow for the in-house introduction of specialized lipophilic scales by transferring routine measurements. While the octanol-water scale is widely applied, it may be advantageous to utilize alternative scales for specific QSAR models. Solvent systems such as alkane or chloroform and biomimetic stationary phases on HPLC columns have both been advocated. Seydel [65] recently reviewed the suitabihty of various systems to describe partitioning into membranes. Through several examples, he concludes that drug-membrane interaction as it relates to transport, distribution and efficacy cannot be well characterized by partition coefficients in bulk solvents alone, including octanol. However, octanol-water partition coefficients will persist in valuable databases and decades of QSAR studies. 

Although the partition coefficient is expected to remain constant, its magnitude is important. Since this coefficient represents the concentration of drug in the membrane relative to that in the core, an excessively high partition coefficient will allow quick depletion of the core and an ineffective delivery system. For effective diffusional systems, the partition coefficient should be less than unity. If the value of this coefficient is greater than 1, the surrounding polymer does not represent a barrier, and drug release becomes first-order. 

Figures 7.31a-c clearly show that after some critical soy content in dodecane, Pe values decrease with increasing soy, for both sink and sinkless conditions. [This is not due to a neglect of membrane retention, as partly may be the case in Fig. 7.23 permeabilities here have been calculated with Eq. (7.21).] Section 7.6 discusses the Kubinyi bilinear model (Fig. 7.19d) in terms of a three-compartment system water, oil of moderate lipophilicity, and oil of high lipophilicity. Since lipo-some(phospholipid)-water partition coefficients (Chapter 5) are generally higher than alkane-water partition coefficients (Chapter 4) for drug-like molecules, soy lecithin may be assumed to be more lipophilic than dodecane. It appears that the increase in soy concentration in dodecane can be treated by the Kubinyi analysis. In the original analysis [23], two different lipid phases are selected at a fixed ratio (e.g., Fig. 7.20), and different molecules are picked over a range of lipophilicities.

In whole tissue or cell monolayer experiments, transcellular membrane resistance (Rm = Pm1) lumps mucosal to serosal compartment elements in series with aqueous resistance (R = P ). The operational definition of Lm depends on the experimental procedure for solute transport measurement (see Section VII), but its magnitude can be considered relatively constant within any given experimental system. Since the Kp range dwarfs the range of Dm, solute differences in partition coefficient dominate solute differences in transcellular membrane transport. The lumped precellular resistance and lumped membrane resistance add in series to define an effective resistance to solute transport ... 

The permeation technique is another commonly employed method for determining the mutual diffusion coefficient of a polymer-penetrant system. This technique involves a diffusion apparatus with the polymer membrane placed between two chambers. At time zero, the reservoir chamber is filled with the penetrant at a constant activity while the receptor chamber is maintained at zero activity. Therefore, the upstream surface of the polymer membrane is maintained at a concentration of c f. It is noted that c f is the concentration within the polymer surface layer, and this concentration can be related to the bulk concentration or vapor pressure through a partition coefficient or solubility constant. The amount... 

The advantage of using the time lag method is that the partition coefficient K can be determined simultaneously. However, the accuracy of this approach may be limited if the membrane swells. With D determined by Eq. (12) and the steady-state permeation rate measured experimentally, K can be calculated by Eq. (10). In the case of a variable D(c ), equations have been derived for the time lag [6,7], However, this requires that the functional dependence of D on Ci be known. Details of this approach have been discussed by Meares [7], The characteristics of systems in which permeation occurs only by diffusion can be summarized as follows ... 

The octanol-water partition coefficient, Kow, is the most widely used descriptor of hydrophobicity in quantitative structure activity relationships (QSAR), which are used to describe sorption to organic matter, soil, and sediments [15], bioaccumulation [104], and toxicity [105 107J. Octanol is an amphiphilic bulk solvent with a molar volume of 0.12 dm3 mol when saturated with water. In the octanol-water system, octanol contains 2.3 mol dm 3 of water (one molecule of water per four molecules of octanol) and water is saturated with 4.5 x 10-3 mol dm 3 octanol. Octanol is more suitable than any other solvent system (for) mimicking biological membranes and organic matter properties, because it contains an aliphatic alkyl chain for pure van der Waals interactions plus the alcohol group, which can act as a hydrogen donor and acceptor. 

Principal differences between bulk media water and membrane water partition coefficients are listed in Table 2. These differences are essentially based on the several orders of magnitude difference in surface-to-volume ratio. In the liposomal system, charges built up due to sorption of charged species can be electrically neutralised by counter-ions from the electrolyte (diffuse double... 

In systems where only dynamic quenching occurs, then steady-state fluorescence intensities can be measured instead of lifetimes/101 103-,07) In experiments where comparisons are being made (i.e., for a comparison of different experimental conditions or types of membrane), it is important that the lifetime of the fluorophore (r0) is not affected by the experimental conditions. Fluorescence intensities can be obtained much more rapidly and without specialized instrumentation. Blatt and Sawyer(101) have employed a relationship essentially the same as Eq. (5.20) in this way. They have pointed out that since the quenching mechanism is collisional, the partition coefficient that is derived is a partition coefficient of the quencher into the immediate environment of the fluorophore and is therefore a local Kp. It is therefore possible to investigate the partition coefficient gradient across the lipid bilayer by using a series of probes, such as the anthroylstearates,(108) located at different depths. In their method, Eq. (5.20) has the form... 

Due to their better biomimetic properties, phospholipids have been proposed as an alternative to 1-octanol for lipophiiicity studies. The use of immobilized artificial membranes (lAM) in lipophiiicity determination was recently reviewed and we thus only briefly summarize the main conclusions [108]. lAM phases are silica-based columns with phospholipids bounded covalently. lAM are based on phosphatidylcholine (PC) linked to a silica propylamine surface. Most lipophiiicity studies with lAM were carried out using an aqueous mobile phase with pH values from 7.0 to 7.4 (log D measurements). Therefore, tested compounds were neutral, totally or partially ionized in these conditions. It was shown that the lipophiiicity parameters obtained on I AM stationary phases and the partition coefficients in 1-octanol/water system were governed by different balance of intermolecular interactions [109]. Therefore the relationships between log kiAM and log Poet varied with the class of compounds studied [110]. However, it was shown that, for neutral compounds with log Poet > 1, a correspondence existed between the two parameters when double-chain lAM phases (i.e., lAM.PC.MG and IAM.PC.DD2) were used [111]. In contrast, in the case of ionized compounds, retention on lAM columns and partitioning in 1 -octanol / water system were significantly different due to ionic interactions expressed in lAM retention but not in 1-octanol/water system and due to acidic and basic compounds behaving differently in these two systems. 

Liao, K. and Yin, M., Individual and combined antioxidant effects of seven phenolic agents in human erythrocyte membrane ghosts and phosphatidylcholine liposome systems importance of the partition coefficient, J. Agric. Food Chem., 48, 2266, 2000. 

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