title: Role of metabolites and calcineurin inhibition on C2 monitoring in renal transplant patients.
abstract: 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.
authors.affiliation: Research Laboratory, Department of Renal Medicine C, Skejby Sygehus, Arhus University Hospital, Arhus, Denmark.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Karamperis
authors.forename: Pernille
authors.initials: P
authors.lastname: Koefoed-Nielsen
authors.forename: Anette
authors.initials: A
authors.lastname: Bagger Sørensen
authors.forename: Carsten
authors.initials: C
authors.lastname: Højskov
authors.forename: Jørgen
authors.initials: J
authors.lastname: Poulsen
authors.forename: Kaj
authors.initials: K
authors.lastname: Jørgensen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016572:Cyclosporine / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; C120817:calcineurin phosphatase; D010744:Phosphoric Monoester Hydrolases