Lipophilicity in trans-bilayer transport and subcellular pharmacokinetics

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