Solubility transcellular passive diffusion

Many drugs are weak electrolytes and their degree of ionization depends on both their pKa and the pH of the solution. Assuming, for transcellular passive diffusion, that the GI tract is acting as a simple lipophilic barrier, the ionized form of a molecule will be more water-soluble and will have negligible lipid solubility in comparison with the unionized, lipid-soluble form, i.e. ... 

The interrelationship between the dissociation constant and lipid solubility of a drag, as well as the pH at the absorption site, is known as the pH-partition theory of drag absorption. Accordingly, rapid transcellular passive diffusion of a drag molecule may be due to ... 

Although it is the ionized form of a drag that is required for aqueous solubility, the unionized form is required for lipid solubility and transcellular passive diffusion. However, the unionized form has poor aqueous solubility, which mitigates against membrane penetration. In practice, a balance between the lipid and aqueous solubility of a drag is required for successful absorption. 

Artificial membranes are a relatively low-cost assay for fast screening of transcellular passive diffusion. The system allows easy access to permeability pH profiles and unstirred water layer correction. Due to the simple composition of the buffer reagents, the analytics is much easier than with cell cultures. Straight UV detection can be used in most cases and LC-MS (low soluble samples or compounds lacking UV chromophore) is considerably simplified in comparison to Caco-2, as the system matrix is relatively simple. A reasonable correlation has been obtained between artificial membrane and reported human GIT permeability in our laboratory (Figure 15.6A). 

For most conventional drag molecules, which tend to be small and lipophilic, absorption occurs transcellularly, via passive diffusion across the epithelial cells. In this case, where the GI tract (or other epithelial interface) is assumed to act as a simple lipophilic barrier, absorption occurs down a concentration gradient according to Fick s Law, and the rate of absorption correlates with the lipid solubility of the drag (see Section 1.3.3.2). 

Hydrophilic compounds may be absorbed via the paracellular route, moving between the epithelial cells via passive diffusion whereas lipid soluble drags are usually absorbed transcellularly, at rates which correlate with their lipid/water diffusion coefficients. Macromolecules may be absorbed via endocytic processes. 

In the majority of cases, drag absorption into the CNS occurs by passive diffusion. The existence of the endothelial tight junctions means that passive diffusion between the cells is prohibited (paracellular route), so that passive diffusion is limited to the transcellular route. Lipid soluble dmgs move across the lipid-rich... 

The unbound drug in the systemic circulation is available to distribute extravascularly. The extent of distribution is mainly determined by lipid solubility and, for weak organic acids and bases, is influenced by the pK3/pH-dependent degree of ionization because only the more lipid-soluble non-ionized form can passively diffuse through cell membranes and penetrate cellular barriers such as those which separate blood from transcellular fluids (cerebrospinal and synovial fluids and aqueous humour). The milk-to-plasma equilibrium concentration ratio of an antimicrobial agent provides a reasonably... 

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