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OtherIMMUNOPHARMACOLOGY

In Vitro Immunosuppressive Activity, Isolation from Pig Liver Microsomes and Identification by Electrospray ms-ms of a New FK-506 C19-C20 Epoxide Metabolite

G. Lhoëst, R. Dieden, R.K. Verbeeck, N. Maton, A. Ingendoh and D. Latinne
Journal of Pharmacology and Experimental Therapeutics March 1998, 284 (3) 1074-1081;
G. Lhoëst
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R. Dieden
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R.K. Verbeeck
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N. Maton
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A. Ingendoh
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D. Latinne
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Abstract

In order to mediate their effects, cyclosporin A and FK-506 must each bind with high affinity to a cytosolic target protein that belongs to the immunophilin group. FK-506 forms complexes with the FK-506 binding protein FKBP, mainly FKBP-12, and these complexes possess immunosuppressive activity through their ability to interact with another target, the abundant serine threonine phosphatase calcineurin. Evaluating the immunosuppressive activities of the FK-506 metabolites by comparing them with known immunosuppressive agents viamixed lymphocyte reaction is of clinical importance because some metabolites may retain the pharmacological activity of the parent drug or exhibit cytotoxic effects. FK-506 is metabolized by the cytochrome P-450-dependent mixed-function oxygenase system in different animal species, and we are reporting the isolation from pig liver microsomes, and the identification by electrospray ms-ms, of the FK-506 C19-C20 epoxide metabolite. We found that this new metabolite exhibits reduced in vitro immunosuppressive activity compared with FK-506 and has approximately the same immunosuppressive potency as other known immunosuppressive drugs, such as cyclosporin A and IMM-125, a hydroxyethyl derivative ofd-serine cyclosporin A. We were able to demonstrate that after incubation of the FK-506 metabolite in human mixed lymphocyte reaction cultures for 6 days, the compound was stable under the conditions used for cell culture as evidenced by electrospray-ms data. A weak direct cytotoxic effect (<30% cell death) was observed only at the highest concentrations (2500 and 5000 ng/ml), which shows that the mixed lymphocyte reaction inhibition cannot be due to a toxic effect.

Footnotes

  • Send reprint requests to: G. Lhoëst, Department of Pharmaceutical Sciences, 7246, Av. E. Mounier, B-1200, Brussels, Belgium.

  • Abbreviations:
    MLR
    mixed lymphocyte reaction
    ms
    mass spectrometry
    NMR
    nuclear magnetic resonance
    CyA
    cyclosporin A
    PBMNC
    peripheral blood mononuclear cells
    LSM
    lymphocyte-separating medium
    MHC
    major histocompatibility complex
    MTT
    3-(4,5-dimethylthiazol-2yl)-2, 5-diphenyl tetrazolium bromide
    PBS
    phosphate-buffered saline
    OD
    optical density
    • Received May 13, 1997.
    • Accepted November 10, 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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OtherIMMUNOPHARMACOLOGY

In Vitro Immunosuppressive Activity, Isolation from Pig Liver Microsomes and Identification by Electrospray ms-ms of a New FK-506 C19-C20 Epoxide Metabolite

G. Lhoëst, R. Dieden, R.K. Verbeeck, N. Maton, A. Ingendoh and D. Latinne
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 1074-1081;

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OtherIMMUNOPHARMACOLOGY

In Vitro Immunosuppressive Activity, Isolation from Pig Liver Microsomes and Identification by Electrospray ms-ms of a New FK-506 C19-C20 Epoxide Metabolite

G. Lhoëst, R. Dieden, R.K. Verbeeck, N. Maton, A. Ingendoh and D. Latinne
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 1074-1081;
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