Constitutive and acquired resistance to calcineurin inhibitors in renal transplantation: role of P-glycoprotein-170.
The present study examines whether resistance to Cyclosporin A (CyA) and Tacrolimus (FK506) develops in T cells from individual patients and the role of P-glycoprotein 170 (P-gp) in mediating drug resistance. IC50s were established for CyA and FK506 in cell cultures from 46 renal allograft recipients. P-gp expression and functional activity were determined by flow cytometry. Mean ID50 for CyA was 29 microg/li (range 2.5-100) and for FK506 1.2 microg/li (range 0.085-5.5). The sensitivities to the two drugs were correlated (P = 0.0001). There was variation in the ratio of the ID50s depending on the drug used for treatment (P = 0.02). There was no difference in P-gp expression and functional activity in patients with sensitive or resistant cells. The data indicate an association between the sensitivities to CyA and FK506 and evidence of selective resistance to whichever drug was used. P-gp drug transport does not explain this variation.
Delaney
M P
MP
Department of Renal Medicine, Walsgrave Hospital, Coventry, West Midlands, UK. delaneymp@doctors.org.uk
Smythe
E
E
Higgins
R M
RM
Morris
A G
AG
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000502:physiology*; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002277:Carcinoma / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000097:blood / Q000627:therapeutic use; D003524:Cyclosporins / Q000494:pharmacology; D004351:Drug Resistance; D004361:Drug Tolerance / Q000502:physiology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000502:physiology; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000187:drug effects; D016559:Tacrolimus / Q000097:blood / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin; C070272:valspodar; D016559:Tacrolimus