Membrane permeation by multidrug-resistance-modulators and non-modulators:Effects of hydrophobicity and electric charge

This study was designed to test the hypothesis that lipophilic cationic dru gs with only roughly similar structures mediate the reversal of multidrug-r esistance (MDR) by interacting with membrane phospholipids. The permeation properties of MDR-modulators and non-modulators were studied by quantifying their ability to induce the leakage of Sulphan blue through the membrane o f negatively charged unilamellar liposomes. Of the 22 compounds under investigation, only those bearing a net positive electric charge per molecule (z) greater than or equal to 0.2 induced dye l eakage. All these efficient drugs are well-known MDR-modulators: calcium-ch annel blockers (propranolol, verapamil, diltiazem and dipyridamole), calmod ulin antagonists (clomipramine and thioridazine) and antiparasitic agents ( mepacrine, thioacridine derivatives and quinine). The non-modulators tested , including antineoplasic agents and steroids, did not induce any membrane permeation. The permeation process was a co-operative one (1.1 < Hill coeff icient < 4.1) and the permeation doses inducing 50% dye leakage (PD50) were 1.9-11.2 mM. The permeation ability of the MDR-modulators (log(1/PD50)) in creased significantly with octanol-buffer distributions per unit net electr ic charge ((logD)/z). The results provide evidence that a complex interplay occurs between the el ectric charge and the lipophilicity of the MDR-modulators when a dye leakag e is induced through model membranes, and probably also when the MDR is rev ersed in leukaemic cells.