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 Ta crolimus (FK506) develops in Tcells from individual patients and the role o f P-glycoprotein 170 (P-gp) in mediating drug resistance. IC(50)s were esta blished for CyA and FK506 in cell cultures from 46 renal allograft recipien ts. P-gp expression and functional activity were determined by flow cytomet ry. Mean LD,, for CyA was 29 mu g/li (range 2.5-100) and for FK5061.2 mu g/ 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 ID(50)s depending on th e drug used for treatment (P = 0.02). There was no difference in P-gp expre ssion and functional activity in patients with sensitive or resistant cells . The data indicate an association between the sensitivities to CyA and FK5 06 and evidence of selective resistance to whichever drug was used. P-gp dr ug transport does not explain this variation.