Co-operative, competitive and non-competitive interactions between modulators of P-glycoprotein

We measured the effects of individual modulators and of pairs of modulators of the multidrug resistance pump, P-glycoprotein, on the accumulation of labelled daunomycin into multidrug-resistant P388 leukemia cells at 37°C and developed a kinetic analysis which enables such data to be modelled in terms of co-operative, competitive or non-competitive interaction between pairs of modulators. The modulators verapamil, cyclosporin and trifluoperazine interacted with P-glycoprotein as single molecules, while vinblastine, mefloquine, dipyridamole, tamoxifen and quinidine displayed Hill numbers close to 2, suggesting that pairs of modulator molecules need to act together in order to bring about effective reversal of P-glycoprotein. When the modulators were presented to P-glycoprotein in pairs, we found examples of both competitive and non-competitive behaviour. We interpret these results on a model in which two modulatory sites exit on the MDR pump. To one of these, mefloquine, vinblastine and tamoxifen bind preferentially; to the other, verapamil, dipyridamole, trifluoperazine and quinidine bind (but mefloquine and tamoxifen only weakly if at all). Cyclosporin A can interact with both sites.