Lipophilicity in trans-bilayer transport and subcellular pharmacokinetics

The aim of subcellular pharmacokinetics in drug design is to model drug disposition and response as a function of the properties of drugs and biosystems involved and the observation time. Biosystems are represented by systems of alternating membranes and aqueous phases that differ in acidity and contain low-molecular cell constituents, enzymes and other proteins. The resulting disposition models are combined with linear free-energy assumptions, drug/receptor binding kinetics and relationships between receptor binding and response to produce model-based quantitative structure-(time-)activity relationships, QS(T)AR. This review summarizes the present status of subcellular pharmacokinetics with emphasis on passive trans-bilayer transport. In particular, mechanisms of transport are analyzed with respect to amphiphilicity and lipophilicity. The overall rate of transport is strongly governed by amphiphilicity, the tendency of drug molecules to adsorb to the bilayer/water interface. Depending on amphiphilicity, the time needed for a drug to cross a single bilayer ranges from seconds to days. The main advantage of the subcellular pharmacokinetic approach is that the resulting models, once calibrated for a given biosystem, provide a detailed recipe for tailoring the drug properties to ensure optimum disposition.