Constitutive and acquired resistance to calcineurin inhibitors in renal transplantation: role of P-glycoprotein-170

Abstract

The present study examines whether resistance to Cyclosporin A (CyA) and Tacrolimus (FK506) develops in T cells from individual patients and the role of Pglycoprotein 170 (P-gp) in mediating drug resistance. IC,,s 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 ID,, for CyA was 29 yg/li (range 2.5-100) and for FK506 1.2 yg/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 ID5,+ 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.

CsA 2-h concentration correlates best with area under the concentration–time curve after allo-SCT compared with trough CsA

“…9 Moreover, measurement of C2 levels or AUC may not be the optimal way of assessing the biological effect of CsA. Significant inter-patient variability in the degree of calcineurin inhibition produced by a consistent dose of CsA 37 has 'emphasised the importance of correlating biological measures of calcineurin inhibition with clinical outcome'. 5 The risk of developing acute GVHD has been reported to correlate with the degree of calcineurin inhibition in mononuclear cells early post transplant, 38 and preliminary data suggest that pharmacodynamic monitoring of the relative reduction of T-cell-specific gene expression in renal transplant patients receiving CsA may be more useful in optimizing CsA dosing than blood levels.…”

Optimizing the use of cyclosporin in allogeneic stem cell transplantation

“…64 There is also emerging evidence that there is significant inter-patient variation in the degree of calcineurin inhibition produced by a consistent dose of CsA, emphasizing the importance of correlating biological measures of calcineurin inhibition with clinical outcome. 65 …”