EFFECT OF CYCLOSPORINE ANALOGS AND FK506 ON TRANSCELLULAR TRANSPORT OF DAUNORUBICIN AND VINBLASTINE VIA P-GLYCOPROTEIN

Purpose. P-glycoprotein-mediated transcellular transport of anticancer agents and the inhibitory effect of cyclosporin analogs and FK506 wer e investigated. Methods. The transcellular transport of daunorubicin a nd vinblastine by monolayers of LLC-GA5-COL150 cells which overexpress ed P-glycoprotein was measured in the presence and absence of cyclospo rins or FK506. Results. Cyclosporins and FK506 inhibited P-glycoprotei n-mediated transport of daunorubicin and vinblastine in the order of c yclosporin D, dihydrocyclosporin D > cyclosporin A > FK506 > cyclospor in C, dihydrocyclosporin C. The intracellular accumulation of the anti cancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect of cyclosporin D was concentrati on-dependent. The inhibitory effect of the modulators on P-glycoprotei n was not correlated with the immunosuppressive activity, but was corr elated with their lipophilicity. Conclusions. In the transcellular tra nsport system, lipophilicity may be one of the determinants for the in hibitory effect of various multidrug resistance modulators on the P-gl ycoprotein-mediated transport.