Schlitt, Hans-Jürgen and Christians, U. and Bleck, J. and Kohlhaw, K. and Ringe, B. and Bunzendahl, H. and Sewing, K. F. and Wonigeit, K. and Pichlmayr, R.
Contribution of cyclosporin metabolites to immunosuppression in liver-transplanted patients with severe graft dysfunction.
Transplant international: official journal of the European Society for Organ Transplantation 4 (1), pp. 38-44.
The aim of this study was to analyse the immunosuppressive contribution of cyclosporin metabolites in liver-grafted patients. Therefore the immunosuppressive potency of 17 metabolites, alone and in combination, was tested in human mixed lymphocyte cultures, and the results were correlated with metabolite blood levels in liver-grafted patients. Of the 17 metabolites tested only six highly lipophilic metabolites showed a detectable immunosuppressive activity of up to 10% of the activity of cyclosporin; the effect of combining metabolites was additive. For calculation of the in vivo activity, blood levels of seven major cyclosporin metabolites were determined in liver-grafted patients with normal liver function (group A, 43 episodes) and with severe hyperbilirubinaemia (group B, 66 episodes). Both patient groups had comparable levels of parent drug (122.9 +/- 17.4 vs. 111.1 +/- 23.5 ng/ml by HPLC) and similar blood levels of the highly lipophilic metabolites 17, 1 and 18. By contrast, blood levels of the less lipophilic metabolites 8, 9, 26 and 203-218 were substantially increased in group B (P less than 0.05). High overall metabolite blood levels in group B were also indicated by a non-specific monoclonal RIA (520 +/- 199 ng/ml for group A vs. 1318 +/- 407 ng/ml for group B). Despite the very high levels in group B, however, the overall contribution of the metabolites to immunosuppression was similar in both groups (12.6 +/- 5.0% for group A vs. 13.8 +/- 5.6% for group B). These findings indicate that, despite a marked accumulation of cyclosporin metabolites in patients with severe cholestatic liver dysfunction, their immunosuppressive contribution remains low.(ABSTRACT TRUNCATED AT 250 WORDS)
|Institutions:|| Medicine > Lehrstuhl für Chirurgie|
|Lymphocyte Culture Test, Mixed||MESH|
|Keywords:||Cyclosporin, role of metabolites, liver transplantation - Metabolites of cyclosporin, in liver transplantation|
|Subjects:||600 Technology > 610 Medical sciences Medicine|
|Created at the University of Regensburg:||Unknown|
|Deposited On:||10 May 2010 12:22|
|Last Modified:||20 Jul 2011 22:28|