Many pharmacologically active compounds are of amphiphilic (or hydrophobic) nature. As a result, they tend to self-associate and to interact with biological membranes. This review focuses on the self-aggregation properties of drugs, as well as on their interaction with membranes. It is seen that drug-membrane interactions are analogous to the interactions between membranes and classical detergents. Phenomena such as shape changes, vesiculation, membrane disruption, and solubilization have been observed. At the molecular level, these events seem to be modulated by lipid flip-flop and formation of non-bilayer phases. The modulation of physicochemical properties of drugs by self-association and membrane binding is discussed. Pathological consequences of drug-membrane interaction are described. The mechanisms of drug solubilization by surfactants are reviewed from the physicochemical point of view and in relation to drug carrying and absorption by the organism.

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A new, simple procedure for the determination of partition coefficients (P) was developed based on spectral effects caused upon addition of solutes to spin labeled model lipid membranes, and on the knowledge of their water solubility. Values of P were determined for nine local anesthetics (LA), amino-esters and amino-amides. The results were in good agreement with those found by phase separation and by a more complex, previously reported, methodology (Lissi et al. (1990) Biochim. Biophys. Acta 1021, 46-50) applied to either EPR or fluorescence spectra of probes incorporated in the bilayers. Both the present and the previously reported procedures make use of effects on membrane structure evaluated by spectroscopic techniques and offer the advantage of not requiring phase separation. The spectral effects, indicative of a decrease in bilayer organization increased with LA concentration, reaching a maximum at the drug water solubility, indicating that partitioning in the membrane is limited by saturation of the aqueous phase. A thermodynamic analysis of the partition data according to Hill (Hill, M.W. (1974) Biochim. Biophys. Acta 356, 117-124) showed that the LAs did not display ideal behavior. Knowledge of the partition coefficients allowed a comparison between effects at the same drug concentration in the membrane. Within a given family (esters, acyclic amides, cyclic amides) no clear proportionality was observed between effect and LA hydrophobicity, as reflected in the partition coefficient. Rather, the membrane perturbing ability is a result of steric effects originating in the mismatch between anesthetic and phospholipid shapes.