Lipoidal/lipid permeability

Lipoidal or lipid permeability has been used to define the disposition characteristics of molecules (Wu and Benet, 2005). This permeability can be related to physicochemical properties as outlined earlier. The relationship can be extended to also the likely interaction sites for a molecule. Small, nonlipophilic molecules will rely on the paracellular pathway. Such molecules will be absorbed from the... 

Four pharmacophores have been identified in CCR5 antagonists 6, namely, a tertiary basic amine, two tail hydrophobes one of which tolerates some polarity, and a (hetero)aryl head (Figure 3.5). In a series of these inhibitors, lipid permeability was very low and strategies to remove the amide function in tail hydrophobe 1 were progressed. Replacement of the secondary amide with a piperidine 7 or azetidine 8 moiety led to the discovery of compounds with increased intrinsic lipoidal membrane permeability and overall an improved in vivo pharmacokinetic profile [7]. 

The rate and extent of intestinal permeation is dependent on the physicochemical properties of the compound (see Sections 16.1.2 and 16.4.3) and the physiological factors. Drugs are mainly absorbed in the small intestine due to its much larger surface area and less tight epithelium in comparison to the colon [17]. The permeation of the intestine may be affected by the presence of an aqueous boundary layer and mucus adjacent to cells, but for a majority of substances the epithelial barrier is the most important barrier to drug absorption. The lipoidal cell membrane restricts the permeability of hydrophilic and charged compounds, whereas large molecules are restricted by the ordered structure of the lipid bilayer. 

The manner of action of narcotics has been discussed extensively, and some of these discussions are relevant to permeability. The adsorption theory of Traube (86) has not proved to be successful in many cases. It seems questionable for ethylene, for reasons just discussed, and probably for the action of ethylene on permeability. The lipoid theory" of narcotics has been advanced by Overton (69) and Meyer (52), and seems stronger. It depends on the correlation between narcotic effect and the distribution coefficients between lipides and water. Those narcotics with higher solubilities in lipides have been widely found to have higher narcotic effects. 

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