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Vol. 284, Issue 3, 817-825, March 1998

Hepatocellular Effects of Cyclosporine A and its Derivative SDZ IMM 125 in Vitro

Armin Wolf, Ursula Schramm, Alfred Fahr, Lothar Aicher, André Cordier, Wolfgang E. Trommer and Gert Fricker

Novartis Pharma AG, Preclinical Safety, Toxicology/Pathology, WS-2881.3.27, CH-4002 Basel (A.W., U.S., L.A., A.C.); Institut für pharmazeutische Technologie und Biopharmazie, D-35032 Marburg (A.F.); Fachbereich Chemie, Universität Kaiserslautern, D-67663 Kaiserslautern (W.E.T.) and Institut für pharmazeutische Technologie und Biopharmazie, D-69120 Heidelberg (G.F.)

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 anisotropy less. Furthermore, SDZ IMM 125 increased Na+ and Ca++ permeability across the liposomal membranes significantly more than CyA. The uptake 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 diffusion coefficient of CyA was about two times higher than that of SDZ IMM 125, reflecting its higher lipophilicity. In primary hepatocyte monolayers the cellular concentrations of CyA were about two times higher than that of SDZ IMM 125. As an indicator of cholestasis the saturable uptake of cholyltaurine into isolated cells was found to be apparently competitively inhibited to the same extent by both compounds. In isolated perfused rat livers SDZ IMM 125 caused a significantly greater decrease in bile flow than did CyA. Release of lactate dehydrogenase from hepatocyte primary cultures and from isolated perfused livers were determined as parameter of cell damage. In both systems the cytotoxicity of SDZ IMM 125 was significantly higher than that of CyA. The data suggest that SDZ IMM 125 causes greater cholestatic and cytotoxic effects than CyA at equimolar cellular exposure.

0022-3565/98/2843-0817$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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S. Grub, E. Persohn, W. E. Trommer, and A. Wolf
Induction of Apoptosis by the O-Hydroxyethyl-D(Ser)8-cyclosporine A Derivative SDZ IMM 125 in Rat Hepatocytes
J. Pharmacol. Exp. Ther., April 1, 2000; 293(1): 24 - 32.
[Abstract] [Full Text]


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