THE ABILITY OF VERAPAMIL TO RESTORE INTRACELLULAR ACCUMULATION OF ANTHRACYCLINES IN MULTIDRUG-RESISTANT CELLS DEPENDS ON THE KINETICS OF THEIR UPTAKE

The basic distinguishing feature of all cells expressing functional P- glycoprotein-multidrug resistance is a decrease of steady state drug l evels as compared to those in drug-sensitive controls. A variety of sm all molecules, such as verapamil and cyclosporin A, bind to P-glycopro tein and inhibit its ability to pump out antitumor drugs. The kinetics of P-glycoprotein-mediated efflux of various anthracycline derivative s was measured in multidrug-resistant (MDR) K562 cells in the presence of verapamil. Used for the purpose were daunorubicin, idarubicin and 8-S-fluoro-idarubicin which have the same pK(a) of deprotonation equal to 8.4, but different lipophilicity, 4'-epi-2'-bromo-daunorubicin whi ch has a lipophilicity which is comparable to that of daunorubicin but a pK(a) equal to 6.3, pirarubicin with pK(a) equal to 7.7 and lipophi licity different from that of these derivatives were used. Our data sh ow (1) that verapamil is unable to completely block the P-glycoprotein -mediated efflux of anthracyclines and that 10% of its functionality r emains even with high verapamil concentrations, (2) that the ability o f verapamil to restore intracellular accumulation of anthracyclines in MDR cells depends on the kinetics of their uptake. With fast kinetics uptake, as is the case for idarubicin, 8-S-fluoro-idarubicin, 4'-epi- 2'-bromo-daunorubicin and pirarubicin (which have either a low pK(a) a nd/or high lipophilicity), verapamil can restore in multidrug resistan t cells an intracellular drug level which is comparable to that observ ed in sensitive cells. This is not possible when the kinetics of uptak e is low as is the case for daunorubicin. Cyclosporin A is a more pote nt modulator and is able to fully restore daunorubicin accumulation in multidrug resistant cells. (C) 1998 Elsevier Science B.V.