Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein

The inhibitory effects of SDZ PSC 833 (PSC833), a non-immunosuppressive cyc losporin derivative, on the P-glycoprotein (P-gp)-mediated transport of dox orubicin and vinblastine were compared with those of cyclosporin A (Cs-A), The transcellular transport of the anticancer drugs and PSC833 across a mon olayer of LLC-GA5-COL150 cells, which overexpress human P-gp, was measured. Both PSC833 and Cs-A inhibited P-gp-mediated transport of doxorubicin and vinblastine in a concentration-dependent manner and increased the intracell ular accumulation of doxorubicin and vinblastine in LLC-GA5-COL150 cells. T he values of the 50%-inhibitory concentration (IC50) of PSC833 and Cs-A for doxorubicin transport mere 0.29 and 3.66 mu M, respectively, and those for vinblastine transport were 1.06 and 5.10 mu M, respectively. The IC50 of P SC833 for doxorubicin transport mas about 4-fold less than that for vinblas tine transport, suggesting that the combination of PSC833 and doxorubicin m ight be effective. PSC833 itself mas not transported by P-gp and had higher lipophilicity than Cs-A. These results indicated that the inhibitory effec t of PSC833 on P-gp-mediated transport was 5- to 10-fold more potent than t hat of Cs-A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P-gp and to the higher lipophilicity of PSC833.