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OtherTOXICOLOGY

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
Journal of Pharmacology and Experimental Therapeutics March 1998, 284 (3) 817-825;
Armin Wolf
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Ursula Schramm
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Alfred Fahr
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André Cordier
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Wolfgang E. Trommer
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Gert Fricker
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. Gert Fricker, Institut für pharmazeutische Technologie und Biopharmazie, INF 366, D-69120 Heidelberg, Germany.

  • Abbreviations:
    CyA
    cyclosporine A
    SDZ IMM 125
    O-hydroxyethyl-d(Ser)8-cyclosporine
    LDH
    lactate dehydrogenase
    ALT
    alanine aminotransferase
    AST
    aspartate aminotransferase
    DPH
    1,6-diphenyl-1,3,5-hexatriene
    DOPC
    dioleyl-phosphatidylcholine
    • Received April 4, 1997.
    • Accepted October 27, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 3
1 Mar 1998
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OtherTOXICOLOGY

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
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 817-825;

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OtherTOXICOLOGY

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
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 817-825;
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