The kinetics of K+ and Na+ transport across the membrane of large unilamellar vesicles (L.U.V.) were compared at two pH's, with two carriers: (222)C10-cryptand (diaza-1,10-decyl-5-hexaoxa-4,7,13,16,21,24-bicyclo[8.8.8.]+ ++hexacosane) and valinomcyin, i.e. an ionizable macrobicyclic amino polyether and a neutral macrocyclic antibiotic. The rate of cation transport by (222)C10 saturated as cation and carrier concentrations rose. The apparent affinity of (222)C10 for K+ was higher and less pH dependent than that for Na+ but resembled the affinity of valinomycin for K+. The efficiency of (222)C10 transport of K+ decreased as the pH fell and the carrier concentration rose, and was about ten times lower than that of valinomycin. Noncompetitive K+/Na+ transport selectivity of (222)C10 decreased as pH, and cation and carrier concentrations rose, and was lower than that of valinomycin. Transport of alkali cations by (222)C10 and valinomycin was noncooperative. Reaction orders in cation n(S) and carrier m(M) varied with the type of cation and carrier and were almost independent of pH; n(S) and m(M) were not respectively dependent on carrier or cation concentrations. The apparent estimated constants for cation translocation by (222)C10 were higher in the presence of Na+ than of K+ due to higher carrier saturation by K+, and decreased as pH and carrier concentration increased. Equilibrium potential was independent of the nature of carrier and transported cation. Results are discussed in terms of the structural, physiocochemical and electrical characteristics of carriers and complexes.

This study was designed to test the hypothesis that lipophilic cationic drugs with only roughly similar structures mediate the reversal of multidrug-resistance (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 of negatively charged unilamellar liposomes. Of the 22 compounds under investigation, only those bearing a net positive electric charge per molecule (z) > or = 0.2 induced dye leakage. All these efficient drugs are well-known MDR-modulators: calcium-channel blockers (propranolol, verapamil, diltiazem and dipyridamole), calmodulin antagonists (clomipramine and thioridazine) and antiparasitic agents (mepacrine, thioacridine derivatives and quinine). The non-modulators tested, including antineoplastic agents and steroids, did not induce any membrane permeation. The permeation process was a co-operative one (1.1< Hill coefficient < 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)) increased significantly with octanol-buffer distributions per unit net electric charge ((logD)/z). The results provide evidence that a complex interplay occurs between the electric charge and the lipophilicity of the MDR-modulators when a dye leakage is induced through model membranes, and probably also when the MDR is reversed in leukaemic cells.

No abstract

Various cationic lipophilic compounds can reverse the multidrug resistance of cancer cells. Possible interaction between these compounds, which are known as modulators, has been assessed by measuring leakage of Sulphan blue from anionic liposomes, induced both by verapamil alone and by verapamil in combination with diltiazem, quinine, thior idazine or clomipramine. An equation was derived to quantify the permeation doses and Hill coefficients of the drugs and mixtures between them by simultaneous fitting of the experimental data. The interaction was tested by two methods, the competition plot and the isobole method; both showed synergy between verapamil and each of diltiazem, qui nine and thioridazine. The dose factor of potentiation for verapamil determined within membranes was 4.0 ± 0.4 with diltiazem, 3.2 ± 0.4 with quinine and 2.4 ± 0.3 with thior idazine. The results suggest that the effectiveness of reversing multidrug resistance may be increased with modulators such as verapamil and diltiazem that have a much greater ef fect in combination than what would be expected from their effects when considered sep arately.