Drug delivery: a process governed by species-specific lipophilicities.

ABSTRACT

Drug delivery is a cascade of molecular migration processes, in which the active principle dissolves in and partitions between several biological media of various hydrophilic and lipophilic character. Membrane penetration and other partitions are controlled by a number of physico-chemical parameters, the eminent ones are species-specific basicity and lipophilicity. Latter is a molecular property of immense importance in pharmacy, bio-, and medicinal chemistry, expressing the affinity of the molecule for a lipophilic environment. This review gives an overview of the types and definitions of the partition coefficient, the most widespread lipophilicity parameter, focusing on the species-specific (microscopic) partition coefficients. We survey the pertinent literature and summarize our recent works that enabled the determination of previously inaccessible species-specific partition coefficients for coexisting, inseparable protonation isomers too. This thorough insight provides explanation why some drugs unexpectedly get into the central nervous system and sheds some light on the submolecular mechanism of pharmacokinetic processes. The contribution of the various ionic forms to the overall partition can now be quantitated. As a result, there is clear-cut evidence that passive diffusion into lipophilic media is not necessarily predominated by the non-charged species, contrary to the widespread misbelief.