Inhibition of the multidrug resistance efflux pump.

An ATP-dependent efflux pump is found in the plasma membrane of certain multidrug resistant (MDR) cancer cells. Drug resistance is due to decreased intracellular drug levels that have been reduced to subcytotoxic concentrations. Inhibition of the MDR efflux pump with a reversal agent may 'trap' the cytotoxic drug inside the cell; thus, cellular drug resistance is reversed. Although many different lipophilic substances exhibit reversal activity, inhibition of the pump is stereospecific with respect to the chiral agent cinchonine. In this article, several methods for the estimation of reversal potency are reviewed. Furthermore, information on the transport characteristics of reversal agents is presented. The rate equations for ATP-dependent drug efflux, competitive inhibition of the MDR pump, and noncompetitive inhibition of the pump are derived. A method is presented that discriminates between competitive or noncompetitive inhibition of the pump. These studies show the potential contribution of fundamental inhibition studies to the design of clinical reversal protocols.