DRUG ACCUMULATION IN THE PRESENCE OF THE MULTIDRUG-RESISTANCE PUMP - DISSOCIATION BETWEEN VERAPAMIL ACCUMULATION AND THE ACTION OF P-GLYCOPROTEIN

We studied the interaction between the multidrug transporter, P-glycop rotein, and two compounds that interact with it: vinblastine, a classi cal substrate of the pump, and verapamil, a classical reverser. Steady -state levels of accumulation of these two drugs were determined in a multidrug resistant P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation a nd the presence of chloroquine on the level of their steady-state accu mulation were quite disparte. Vinblastine inhibited the accumulation o f verapamil whereas it enhanced the accumulation of daunomycin, anothe r classic substrate of P-glycoprotein. Verapamil did not compete with the intracellular binding sites of vinblastine. In all aspects, vinbla stine behaved as a typical substrate of P-glycoprotein but verapamil d id not. Our data suggest that verapamil is a reverser of P-glycoprotei n but that its intracellular accumulation is not effected by this memb rane-bound transporter.