Lipid Lipid/water partition coefficients,

The simplest way to predict the lipid/ water partition coefficient, Kiw, of a drug is based on measurements of the surface pressure, ttd, of the drug as a function of its concentration in the aqueous subphase (Gibbs adsorption isotherm). The Gibbs adsorption isotherm provides the air/water partition coefficient, Kaw, and the cross-sectional area, Ad of the drug and allows calculation of the lipid/water partition coefficient, K]w, according to Eq. (6) [59] ... 

The presence of a transporter can be assessed by comparing basolateral-to-apical with apical-to-basolateral transport of substrates in polarized cell monolayers. If P-gp is present, then basolateral-to-apical transport is enhanced and apical-to baso-lateral transport is reduced. Transport experiments are in general performed with radioactively labeled compounds. Several studies have been performed with Caco-2 cell lines (e.g. Ref. [85]). Since Caco-2 cells express a number of different transporters, the effects measured are most probably specific for the ensemble of transporters rather than for P-gp alone. P-gp-specific transport has been assayed across confluent cell layers formed by polarized kidney epithelial cells transfected with the MDR1 gene [86], Figure 20.11 shows experimental data obtained with these cell lines. A rank order for transport called substrate quality was determined for a number of compounds [86]. The substrate quality is a qualitative estimate, but nevertheless allows an investigation of the role of the air/water (or lipid/water) partition coefficient, log Kaw, for transport as seen in Fig. 20.11(A). For most of the compounds, a linear correlation is observed between substrate quality and log Kaw- However, four compounds are not transported at all despite their distinct lipophilicity. A plot of the substrate quality as a function of the potential of a... 

Compounds with a high H-bond acceptor potential (EUh > 8) (e.g., cyclosporine A, SDZ PSC-833) act as competitive inhibitors, presumably because they occupy all H-bond donor sites of the transporter. Due to the strong interaction of these compounds with P-gp they are transported slowly, and this is reflected in a low rate of ATP hydrolysis. Many of these compounds exhibit high lipid/water partition coefficients and thus also low K, values. 

Tab. 20.2. Drug properties which influence the lipid/water partition coefficient, K w and the transporter binding constant, Kt.

I. Lipid-soluble drugs cross the membrane at a rate proportional to the concentration gradient across the membrane and the lipid water partition coefficient of the drug... 

The specific mechanisms by which mirex and chlordecone are transferred from the gut, lungs, or skin to the blood are not known. However, mirex is a highly stable, lipophilic compound that is resistant to metabolism. It has a high lipid water partition coefficient, so it partitions readily into fat and demonstrates a very high potential for accumulation in tissues. The preferential distribution of chlordecone to the liver rather than to the fat tissue is due to its association with plasma proteins. 

Toropov AA, Roy K (2004) QSPR modeling of lipid-water partition coefficient by optimization of correlation weights of local graph invariants. J. Chem. Inf. Comput. Sci. 44 179-186. 

Combining the equation for the diffusion coefficient with a Collander-type expression for the lipid-water partition coefficient resulted in an expression for calculating the permeability across the stratum corneum ... 

Figure 6.13 Chemical concentrations sufficient to immobilize tadpoles, and their lipid/water partition coefficients...

Most drugs pass through membranes by passive diffusion (down their concentration gradient) of the unionized moiety. The rate of diffusion depends mainly on the lipid-water partition coefficient rather than on lipid solubility per se. For example, the central nervous sys-... 

Pulmonary absorption of volatile anesthetics across the alveolar-capillary barrier is very rapid because of the relatively high lipid-water partition coefficients and small molecular radii of such agents. The driving force for diffusion is a combination of the blood-air partition coefficient (which is a measure of the capacity of blood to dissolve drug) and the difference in partial pressure between the alveoli and the arterial and venous blood. Agents with high blood-air partition coefficients require more drug to be dissolved in the blood for equilibrium to be reached. 

Lipid-water partition coefficient and octanol-water partition constant gKmpw = a ogKiow + b 10... 

In most cases we can assume that the equilibrium distribution and partitioning of organic chemicals in both mammalian and nonmammalian systems is a function of lipid content in the animal and that the lipid-water partition coefficient (AW) is equal to K0w Instances where this is not the case include specific binding sites (e.g., kepone in the liver) and nonequilibrium conditions caused by slow elimination rates of higher level organisms or structured lipid phases that sterically hinder accumulation of very hydrophobic chemicals. For aquatic organisms in constant contact with water, the bioconcentration factor or fish-water partition coefficient (AW) s simply ... 

In addition to the lipid-water partition coefficient, other factors that control the rate of absorption of drugs are the degree of ionization, the surface area, blood flow through the region, and the gastric emptying time. 

Bioconcentration in aquatic macrophytes also has been described by equilibrium partitioning of chemical between the macrophytes lipid or organic carbon fraction and water (e.g., Gobas et al., 1991). If the lipid-water partition coefficient is used to describe the partitioning of chemical between macrophytes and water, then the chemical concentration in macrophytes (CM, g chemical/kg organism) is approximately equal to the product of the freely dissolved chemical concentration in water (CWT), g chemical/L water), the lipid content of the macrophytes (LM, kg lipid/kg organism), and the lipid-water partition coefficient (K L water/kg lipid), which Kow can approximate ... 

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