INHIBITION BY RAPAMYCIN OF P-GLYCOPROTEIN 170-MEDIATED EXPORT FROM NORMAL LYMPHOCYTES

P-glycoprotein 170 encoded by the MDR-1 gene mediates export of substr ates including some immunosuppressive drugs. Rapamycin was compared to cyclosporine A for its ability to inhibit P-glycoprotein on normal hu man peripheral blood mononuclear cells (PBMC). Rhodamine 123 dye efflu x measures P-glycoprotein activity and inhibition of P-glycoprotein re sults in dye retention. Normal CD4(+), CD8(+) and B cells include a su bstantial subset with cyclosporine A-sensitive rhodamine efflux. Rh123 dye efflux is also inhibited by rapamycin at comparable drug levels u sed in transplant models. CsA is approximately 100-fold more effective on inhibition of PBMC P-gp than is RAPA. P-glycoprotein inhibition of ex vivo lymphocytes with three multi-drug resistant T-cell lines show ed susceptibility of P-glycoprotein to rapamycin dependent on the cell type. Compared to cyclosporine A, the reduced ability of rapamycin to inhibit P-glycoprotein reflects a reduced avidity in its binding to P -glycoprotein and perhaps increased access to the cell interior. The i ncreased efficiency of RAPA as an immunosuppressive may in part be a r esult of its relatively low avidity for P-glycoprotein. The authors sp eculate that interactions with P-glycoprotein may partially modulate t he immunosuppressive effects of rapamycin.