Thermal dependence of multidrug-resistant-modulator efficiency: a study in anionic liposomes.

This study was designed to test the hypothesis that there exists a correlation between the ability of lipophilic drugs to mediate the reversal of multidrug-resistance (MDR) by interacting with the membrane phospholipids and the metabolic level in tissues. The permeation properties of five MDR-modulators were studied by quantifying their ability to induce the leakage of Sulphan blue through unilamellar liposomes, over the temperature range 27-42 degrees C. The dye leakage induced by a non-ionic detergent (Triton X-100), two calcium blockers (diltiazem and verapamil) and two antiparasitic agents (thioacridine derivative and mepacrine) was temperature-dependent. The permeation process was a co-operative one (1.1 < Hill coefficient < 7.5) and the permeation doses inducing 50% dye leakage (PD50) were 1.5 - 14.9 mM. The permeation ability of the MDR-modulators (log(1/PD50)) decreased significantly as the net electric charge (z) increased. The passive dye leakage (deltaG < 0) was found to be an endothermic process (deltaH > 0), favoured by an increase in the membrane disorder (deltaS > 0). The apparent enthalpy factor (deltaH50) associated with 50% dye leakage increased with the net electric charge of the compound, and this energetically non-favoured event was entirely offset by the concomitant increase in the entropy factor (deltaS50). The apparent permeation enthalpy (deltaH50) and entropy (deltaS50) showed the lowest values for Triton X-100 (deltaH50 = 7.1 +/- 0.53 kJ mol(-1), deltaS50 = 76.9 +/- 1.86 Jmol(-1) K(-1)), and the highest values for mepacrine (deltaH50 = 79.5 +/- 3.80 kJmol(-1), deltaS50 = 306.7 +/- 5-97 J mol(-1) K(-1)). When the temperature was increased from 27 to 42 degrees C, the apparent Gibbs free energy (deltaG50) of the dye leakage induced by Triton X-100 decreased by less than 10% of the initial value, and that induced by mepacrine decreased by nearly 40%. The results provide evidence that in tissues with high metabolic levels and therefore high temperatures, MDR-reversal is likely to be enhanced via favourable drug-membrane interactions controlled by the electric charge of the modulators.