KINETIC-PARAMETERS FOR REVERSAL OF THE MULTIDRUG PUMP AS MEASURED FORDRUG ACCUMULATION AND CELL-KILLING

We determined the kinetic parameters that describe the effect of 20 di fferent modulators of the multidrug resistance pump on the reversal of cytotoxin accumulation in a resistant strain of P388 leukemia cells ( P388/ADR), and on the reversal of cell killing for these cells. When m easured by a direct comparison of the amplitude of the pertinent proto col (accumulation or cell killing), the K-i for reversal of accumulati on was generally some four or five times larger than that for reductio n of cytotoxicity. We showed that this was only an apparent discrepanc y, since a full theoretical analysis of the two protocols allowed the intrinsic K-i to be obtained for the two procedures and these computed K-i values were then almost identical. We found that for six of the m odulators studied (namely, cyclosporin A, quinidine, dipyridamole, pro pafenone, mefloquine, tamoxifen) the extent of pump reversal should be better than 90% at tolerated plasma levels culled from the literature .