Reduced cyclosporin accumulation in multidrug-resistant cells.
Cyclosporin accumulation was reduced by 50% or more in multidrug- resistant CHRC5 CHO cells with high levels of P-glycoprotein expression compared to drug sensitive AuxB1 CHO cells. This difference could be overcome by verapamil which is known to interact with P-glycoprotein and reverse multidrug resistance. The difference in cyclosporin accumulation between sensitive and resistant cells decreased with increasing cyclosporin concentrations suggesting that cyclosporine itself regulated its own accumulation through interaction with P-glycoprotein. Indeed, cyclosporin also reversed differences in vinblastine accumulation between resistant and sensitive cell lines. Since P-glycoprotein is highly expressed in the kidney which is also a target for cyclosporin toxicity, the effects of verapamil on cyclosporin accumulation were studied in two renal cell lines, rat mesangial cells and LLCPK1, cells. Verapamil increased cyclosporin accumulation by approximately 70%. These results suggest that cellular cyclosporine accumulation is regulated at least in part by its interaction with P-glycoprotein.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002460:Cell Line; D003524:Cyclosporins / Q000378:metabolism*; D004351:Drug Resistance; D008562:Membrane Glycoproteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D014747:Vinblastine; D014700:Verapamil