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.