Inhibitory Effects of a Cyclosporin Derivative, SDZ PSC 833, on Transport of Doxorubicin and Vinblastine via Human P‐Glycoprotein

Abstract

The inhibitory effects of SDZ PSC 833 (PSC833), a non-immunosuppressive cyclosporin derivative, on the P-glycoprotein (P-gp)-mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs-A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer 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 intracellular accumulation of doxorubicin and vinblastine in LLC-GA5-COL150 cells. The values of the 50%-inhibitory concentration (IC 50 ) of PSC833 and Cs-A for doxorubicin transport were 0.29 and 3.66 µ µ µ µM, respectively, and those for vinblastine transport were 1.06 and 5.10 µ µ µ µM, respectively. The IC 50 of PSC833 for doxorubicin transport was about 4-fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P-gp and had higher lipophilicity than Cs-A. These results indicated that the inhibitory effect of PSC833 on P-gp-mediated transport was 5-to 10-fold more potent than that 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.

Effect of PCB-126 on Intracellular Accumulation and Transepithelial Transport of Vinblastine in LLC-PK1 and Its Transformant Cells Expressing Human P-Glycoprotein

“…The net basal-to-apical transport of vinblastine in the monolayer cells increased in LLC-MDR1 compared to LLC-PK1 as reported earlier [10,19], thus indicating that the P-glycoprotein was responsible for the net basal-to-api- cal transepithelial transport. By adding CYA and PCB-126 to the basal side of the monolayer of LLC-MDR1, the basalto-apical transports were increased, thereby increasing the net basal-to-apical transepithelial transports.…”

“…The increase in the accumulation of vinblastine by adding CYA in LLC-MDR1 might be considered due to the inhibition of the extrusion through P-glycoprotein binding with CYA as reported earlier [19,25]. Nevertheless, the effect of CYA was detected not only in LLC-MDR1 but also in LLC-PK1, and the absolute magnitude of the inhibition with CYA was greater in LLC-PK1 than in LLC-MDR1.…”

“…Here we report the effect of PCB-126 on the accumulation and transepithelial transport of vinblastine in a porcine kidney epithelial cell line, LLC-PK1, and its transformant cells expressed with human P-glycoprotein. Vinblastine is among the anticancer drugs, which has been well examined as a substrate of P-glycoprotein for transport [15,19,29]. Cyclosporine A (CYA) was employed as a positive control for an inhibitor of P-glyco-protein, which has been shown to compete with vinblastine for a binding site of P-glycoprotein [25].…”

The Novel Anticancer Drug KRN5500 Interacts with, but is Hardly Transported by, Human P‐Glycoprotein

“…9,10) It is important to determine whether anticancer drugs are substrates for P-gp, since substrates can be unexpectedly ineffective in such patients. The substrates for P-gp include vinblastine 11,12) and doxorubicin, 12) as well as the cardiac glycoside digoxin 13,14) and the immunosuppressive agent cyclosporin A. 15) It has been demonstrated in vitro that the cellular accumulation of vinblastine and doxorubicin is reduced 11,12) and they are not effective in P-gp-expressing MDR cells.…”

“…The substrates for P-gp include vinblastine 11,12) and doxorubicin, 12) as well as the cardiac glycoside digoxin 13,14) and the immunosuppressive agent cyclosporin A. 15) It has been demonstrated in vitro that the cellular accumulation of vinblastine and doxorubicin is reduced 11,12) and they are not effective in P-gp-expressing MDR cells. Even for drugs that are substrates for P-gp, it should be clarified whether they are indeed transported by P-gp.…”