title: Inhibition by rapamycin of P-glycoprotein 170-mediated export from normal lymphocytes.
abstract: P-glycoprotein 170 encoded by the MDR-1 gene mediates export of substrates including some immunosuppressive drugs. Rapamycin was compared to cyclosporine A for its ability to inhibit P-glycoprotein on normal human peripheral blood mononuclear cells (PBMC). Rhodamine 123 dye efflux measures P-glycoprotein activity and inhibition of P-glycoprotein results in dye retention. Normal CD4+, CD8+ and B cells include a substantial subset with cyclosporine A-sensitive rhodamine efflux. Rh123 dye efflux is also inhibited by rapamycin at comparable drug levels used 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 showed 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 increased efficiency of RAPA as an immunosuppressive may in part be a result of its relatively low avidity for P-glycoprotein. The authors speculate that interactions with P-glycoprotein may partially modulate the immunosuppressive effects of rapamycin.
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Canada.
authors.forename: B R
authors.initials: BR
authors.lastname: Yacyshyn
authors.forename: M B
authors.initials: MB
authors.lastname: Bowen-Yacyshyn
authors.forename: L M
authors.initials: LM
authors.lastname: Pilarski
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D011090:Polyenes / Q000494:pharmacology*; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D020123:Sirolimus; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D011090:Polyenes; D012235:Rhodamines; D020112:Rhodamine 123; D016572:Cyclosporine; D020123:Sirolimus