THE ROLE OF DRUG LIPID INTERACTIONS IN THE BIOLOGICAL-ACTIVITY OF MODULATORS OF MULTIDRUG-RESISTANCE

Of the compounds that have now been shown to circumvent acquired cellu lar multidrug resistance, little or no structure-activity relationship has been found, although their proposed mechanism of action is throug h modulation of function of p-glycoprotein. While it has been suggeste d that this inhibition is a direct binding to p-glycoprotein, we show here that such a model seriously neglects the effects many of these co mpounds have on lipid physical properties. We have characterized the i nteractions between 16 structurally diverse pharmacological agents (ni ne of which are known to reverse multidrug resistance) and a variety o f lipids. Potent modulators inhibit the membrane binding of rhodamine 6G, and we have observed a correlation of the measured K-i values with the effectiveness of the compounds in situ. We have determined the ef fects of the compounds on detergent micellization, and have shown subs tantial changes on the critical micelle concentration of detergents in the presence of modulators. Finally, we have examined the changes in model membrane 'viscosity' induced by the compounds. These results ind icate that both direct p-glycoprotein and indirect lipid interactions of modulators should be considered in the mechanism by which these com pounds reverse multidrug resistance.