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Journal of Pharmacology and Experimental Therapeutics

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OtherIMMUNOPHARMACOLOGY

Discovery of Less Nephrotoxic FK506 Analogs and Determining Immunophilin Dependence of Immunosuppressant Nephrotoxicity with a Novel Single-Dose Rat Cisplatin Potentiation Assay

Karl W. Mollison, Thomas A. Fey, Ruth A. Krause, Janet M. Andrews, Pat T. Bretheim, Julie A. Brandt, Megumi Kawai, Rolf Wagner, Gin C. Hsieh and Jay R. Luly
Journal of Pharmacology and Experimental Therapeutics December 1997, 283 (3) 1509-1519;
Karl W. Mollison
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Thomas A. Fey
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Ruth A. Krause
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Janet M. Andrews
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Pat T. Bretheim
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Julie A. Brandt
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Megumi Kawai
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Rolf Wagner
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Gin C. Hsieh
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Abstract

Comparing nephrotoxicity of numerous drug analogs is impractical with chronic in vivo models. We devised a new cisplatin potentiation assay (CISPA) that sensitively detects renal injury as a serum creatinine increase when only one dose of test compound is followed by cisplatin. Reference nephrotoxins known to act on various sites in kidney tubules, glomeruli or renal papilla were all detected by the CISPA at single doses that without cisplatin gave little change, which showed that this simple, sensitive assay has broad potential utility for mechanistic studies of nephrotoxicity. We used the CISPA both to probe the nephrotoxic mode of action of immunosuppressants and to search for safer compounds. Although several non-nephrotoxic immunosuppressants were inactive, cyclosporine, FK506, ascomycin (C21-ethyl-FK506) and rapamycin were nephrotoxic in the CISPA at single doses equal to the daily amounts required to reduce creatinine clearance with 14 days of treatment. Similar therapeutic indices were derived comparing toxicity by either method to prevention of rat ear-heart allograft rejection. C18-OH-ascomycin, an FK506-binding protein (FKBP) antagonist, reversed in vivoimmunosuppression by FK506 and ascomycin in the rat, and pretreatment in the CISPA blocked FK506 and ascomycin nephrotoxicity, which showed a common immunophilin dependence. Rapamycin nephrotoxicity was unaffected (as with cyclosporine), which indicated that binding to FKBP was not required. Rapamycin nephrotoxicity thus appears mechanistically unrelated to its immunosuppressive mode of action. Screening with the CISPA enabled discovery of A-119435, a less nephrotoxic ascomycin analog having a 10-fold higher therapeutic index.

Footnotes

  • Send reprint requests to: Karl Mollison, D-47L AP9, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500.

  • Abbreviations:
    2-BEA-HBr
    2-bromoethanamine hydrobromide
    ASCO
    ascomycin
    CISPA
    cisplatin nephrotoxicity potentiation assay
    cisplatin
    cis-platinum (II) diammine dihydrochloride
    CsA
    cyclosporine
    FKBP
    FK506 binding protein
    GFR
    glomerular filtration rate
    HCBD
    hexachlorobutadiene
    mpk
    mg/kg body weight
    PLN
    popliteal lymph node
    RAPA
    rapamycin
    BUN
    blood urea nitrogen
    • Received April 17, 1997.
    • Accepted August 8, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 3
1 Dec 1997
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OtherIMMUNOPHARMACOLOGY

Discovery of Less Nephrotoxic FK506 Analogs and Determining Immunophilin Dependence of Immunosuppressant Nephrotoxicity with a Novel Single-Dose Rat Cisplatin Potentiation Assay

Karl W. Mollison, Thomas A. Fey, Ruth A. Krause, Janet M. Andrews, Pat T. Bretheim, Julie A. Brandt, Megumi Kawai, Rolf Wagner, Gin C. Hsieh and Jay R. Luly
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1509-1519;

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OtherIMMUNOPHARMACOLOGY

Discovery of Less Nephrotoxic FK506 Analogs and Determining Immunophilin Dependence of Immunosuppressant Nephrotoxicity with a Novel Single-Dose Rat Cisplatin Potentiation Assay

Karl W. Mollison, Thomas A. Fey, Ruth A. Krause, Janet M. Andrews, Pat T. Bretheim, Julie A. Brandt, Megumi Kawai, Rolf Wagner, Gin C. Hsieh and Jay R. Luly
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1509-1519;
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