Effect of cyclosporin and verapamil on the cellular kinetics of daunorubicin.

Both cyclosporin and verapamil modulate the multidrug-resistant (MDR) phenotype in the classical MDR cell lines, CEM/VLB100 and CEM/VLB1000. Initial studies demonstrated a significant reduction in daunorubicin accumulation in the two resistant lines compared with the drug-sensitive parent line CEM/CCRF. Both cyclosporin and verapamil increased drug accumulation in the resistant lines. This effect was dose-dependent although a plateau occurred in CEM/VLB100 cells at concentrations of cyclosporin exceeding 4.2 mumol/l. Cyclosporin 4.2 mumol/l and verapamil 10 mumol/l significantly increased daunorubicin uptake and reduced drug efflux in the CEM/VLB100 and CEM/VLB1000 lines. At low clinical concentrations of cyclosporin (0.8-1.6 mumol/l and verapamil (1-2 mumol/l), there was a synergistic increase in drug accumulation in the two resistant cell lines (P less than 0.007). These data suggest that cyclosporin modulates the classical MDR phenotype by altering the cellular kinetics of daunorubicin. The in vitro synergistic action of cyclosporin and verapamil could be interesting clinically.