HEPATOCELLULAR EFFECTS OF CYCLOSPORINE-A AND ITS DERIVATIVE SDZ IMM-125 IN-VITRO

The novel immunosuppressive drug O-hydroxyethyl-D(Ser)(8)-cyclosporine (SDZ IMM 125) and cyclosporine A (CyA) were compared in different in vitro models with respect to hepatocellular side effects. SDZ IMM 125 was less lipophilic than CyA and also decreased liposomal membrane ani sotropy less. Furthermore, SDZ IMM 125 increased Na+ and Ca++ permeabi lity across the liposomal membranes significantly more than CyA. The u ptake of CyA and SDZ IMM 125 into freshly isolated rat hepatocytes was neither saturable, Na+ dependent or temperature sensitive, nor could it be inhibited vice versa, indicating passive diffusion. The diffusio n coefficient of CyA was about two times higher than that of SDZ IMM 1 25, reflecting its higher lipophilicity. In primary hepatocyte monolay ers the cellular concentrations of CyA were about two times higher tha n that of SDZ IMM 125. As an indicator of cholestasis the saturable up take of cholyltaurine into isolated cells was found to be apparently c ompetitively inhibited to the same extent by both compounds. In isolat ed perfused rat livers SDZ IMM 125 caused a significantly greater decr ease in bile flow than did CyA. Release of lactate dehydrogenase from hepatocyte primary cultures and from isolated perfused livers were det ermined as parameter of cell damage. In both systems the cytotoxicity of SDZ IMM 125 was significantly higher than that of CyA. The data sug gest that SDZ IMM 125 causes greater cholestatic and cytotoxic effects than CyA at equimolar cellular exposure.