Reflection coefficient partition/permeability

The partition coefficient, which will be described in more detail later in this chapter, is the relative solubility of the compound in lipid and water, and the compound s solubility really reflects the ability of the toxicant to move from a relatively aqueous environment across a lipid membrane. It is this factor that is often manipulated in pesticide and drug formulations to create a vehicle. Membrane permeability is therefore strongly correlated to the lipid solubility of the toxicant in the membrane as well as... 

In an in vitro experiment using Fischer 344 rat skin, the partition coefficient for skin air was determined for benzene at 203 ppm (Mattie et al. 1994). The partition coefficient of a chemical in skin is an indicator of the capacity of the skin for the chemical, and may reflect the rate at which a chemical is absorbed through the skin and enters the circulation. Results indicated a partition coefficient of 35, with an equilibration time of 4 hours. This value more closely correlates with the permeability constant of 1.5 derived by McDougal et al. (1990), than does the commonly used octanol/water partition coefficient of 134.9, as derived by Leo et al. (1971). The skin air partition coefficient is necessary for developing the dermal compartment of a PBPK model. 

However, more important physicochemical properties in terms of ocular bio-availability are the ones that affect the corneal permeability of the active compound. These include the lipophilicity of the drug as reflected by its n-octanol-water partition coefficient [32], the molecular size and shape [33], the charge [34], and the acid-base properties as determined by its pK [35]. 

This relationship between the permeability values of several compounds (p) and the partition coefficient of these compounds between the ionic liquid phase immobilized on the membrane and the feed/receive phase (K) has been examined by several authors [16, 18]. The increase in the K values for the compounds was reflected in an increase in the p values. A mathematical correlation between these parameters has been established by de los Rios et al. [22], given in Eq. 11.2 ... 

Three major variables account for differences in the rate at which different compounds permeate the skin the concentration of permeant applied, the partition coefficient of the permeant between the stratum corneum lipids and the vehicle and the diffusivity of the compound within the stratum corneum. For a homologous series of chemicals, such as the alkanols, in which lipid/water partition coefficients increase exponentially with increasing alkyl chain length (Flynn and Yalkowski 1972) and for permeation through a lipid membrane of fixed or normalized thickness, the permeability coefficients will directly reflect partitioning... 

Figure 6 shows the effects of a homologous series of alkyl sulfates and alkyl car-boxylates on the permeability properties of porcine skin to water. Consistent with the findings of others, maximal tissue damage was observed for the C12 species. This maximum reflects a delicate balance between several mutually exclusive forces. For example, lipo-philicity and the ability to partition into a oil phase increases with alkyl chain length. However, offsetting these effects are the limitations imposed by decreases in solubility and permeability coefficients due to increasing molecular size [130]. 

However, the octanol/water partition coefficients do not completely reflect BBB permeability to solutes. Some solutes with low partition coefficients that easily enter into the CNS generally cross the BBB by active or facilitated transport mechanisms, which rely on ion channels, specific transporters,... 

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