Effect of modulators of the multidrug resistance pump on the distribution of vinblastine in tissues of the mouse.

Abstract

Vinblastine at doses ranging from 0.2 to 6 mg/kg body weight was administered i.p. to mice in the absence or presence of the drugs PSC 833, cyclosporin A, mefloquine, quinidine and dipyridamole, all compounds that modulate the multidrug resistance pump and thus increase the accumulation of this cytotoxin in drug-resistant cells in cell culture. In the absence of modulators, vinblastine accumulated in tissues to different extents--lowest in brain, highest in pancreas and intestine. The extent of accumulation was directly proportional to the vinblastine dose in the range 0.2-6 mg/kg body weight. Both at high and low vinblastine doses, all the modulators except quinidine increased the ability of liver, kidney, intestine and lung to accumulate vinblastine by up to 5-fold, and with the further exception of mefloquine, also increased vinblastine levels in pancreas. Only dipyridamole had a marked effect also in brain. Cyclosporin A provided effective increases in the tissue distribution of vinblastine at plasma concentrations similar to those needed to block the multidrug pump in the case of cells in cell culture. For mefloquine, plasma concentrations three or four times higher were needed in vivo than were found to be effective in cell culture. The mouse system provides a quick and reliable in vivo method to assay modulators before they are tested in the clinic.