NDT Advance Access originally published online on January 25, 2005
Nephrology Dialysis Transplantation 2005 20(3):618-621; doi:10.1093/ndt/gfh671
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Role of metabolites and calcineurin inhibition on C2 monitoring in renal transplant patients
1 Research Laboratory, Department of Renal Medicine C and 2 Department of Clinical Chemistry, Århus Kommunehospital, Århus University Hospital, Århus, Denmark
Correspondence and offprint requests to: Kaj Jørgensen, Research Laboratory, Department of Renal Medicine C, Skejby Sygehus, Århus University Hospital, Århus, Denmark. E-mail: kaj{at}dadlnet.dk
Background. Many transplantation centres have switched to C2 monitoring of cyclosporin-treated renal transplant patients. The rationale is that the C2 correlates best with AUC0–4 (area under the concentration–time curve), which again correlates with rejection and nephrotoxicity. It has also been demonstrated that calcineurin phosphatase is inhibited maximally 1–2 h after intake of cyclosporin in patients receiving their first dose. Cyclosporin is metabolized to many compounds, which may influence the results of immunoassays. Some metabolites may have immunosuppressive activity.
Methods. Cyclosporin metabolites were added to whole blood from healthy volunteers and the calcineurin phosphatase activity (CaN) was determined. Twenty renal transplant patients at varying times after transplantation had blood samples drawn in the morning before and 1, 2, 3 and 4 h after intake of their usual dose of cyclosporin microemulsion. Whole blood samples were analysed by liquid chromatography/tandem mass spectrometry for cyclosporin blood concentration and for the cyclosporin metabolites AM1, AM9, AM1c and AM4n. All samples were analysed for CaN utilizing a 32P-labelled 19 amino-acid peptide.
Results. The concentrations of AM1c and AM4n were very low and cannot contribute to CaN inhibition. The ratio of AM1 and AM9 to cyclosporin was high before intake of the drug, but it was much lower during the following 4 h. The 2-h values of cyclosporin were the best predictors of AUC0–4. Calcineurin phosphatase was most inhibited in the 2-h samples and the 2-h value of CaN was the best predictor of CaN AUC0–4. The correlation with calcineurin inhibition seemed better for cyclosporin plus metabolites than for cyclosporin.
Conclusions. Samples collected at 2 h are the best predictors of AUC0–4 for both cyclosporin and calcineurin inhibition. The impact of metabolites appears to be small; however, the temporal profile of calcineurin inhibition seemed to follow cyclosporin plus metabolites better than cyclosporin alone.
Keywords: AUC0–4; C2 monitoring; calcineurin activity; cyclosporin; metabolites
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