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Research ArticleArticle

Bioactivation and Covalent Binding of Hydroxyfluperlapine in Human Neutrophils: Implications for Fluperlapine-Induced Agranulocytosis

W. George Lai, Iain Gardner, Nasir Zahid and Jack P. Uetrecht
Drug Metabolism and Disposition March 2000, 28 (3) 255-263;
W. George Lai
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Iain Gardner
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Nasir Zahid
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Jack P. Uetrecht
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Abstract

The use of fluperlapine and the structurally related clozapine has been associated with the induction of agranulocytosis in humans. Unlike clozapine, fluperlapine is relatively resistant to chemical and biochemical oxidations. In this study we demonstrated that 7-hydroxyfluperlapine, the major metabolite of fluperlapine in humans, is oxidized to a reactive intermediate by HOCl and by myeloperoxidase in the presence of H2O2 and Cl−. This reactive intermediate was identified as an iminoquinone species with a M + 1 ion at m/z 324 by mass spectrometry. The iminoquinone intermediate was trapped byN-acetyl-l-cysteine (NAC) as well as GSH. NMR spectra of the NAC adducts indicated that the NAC was bound to the 6 and 9 positions of the aromatic ring. This is the same orientation as the binding of nucleophiles to the reactive metabolite of clozapine. We were able to use an antibody against clozapine to demonstrate that 7-hydroxyfluperlapine, but not fluperlapine itself, covalently modifies human myeloperoxidase. Furthermore, we demonstrated that 7-hydroxyfluperlapine is metabolized by activated neutrophils to a reactive intermediate that covalently binds to neutrophils. In the presence of NAC or GSH, such covalent binding was inhibited and the NAC or GSH adducts were formed. Thus, the reactivity and even the orientation of the binding of the reactive metabolite of 7-hydroxyfluperlapine is very similar to that of clozapine. These results provide a mechanism for the formation of a reactive metabolite of fluperlapine similar to clozapine that may explain its ability to induce agranulocytosis.

Footnotes

  • Send reprint requests to: Dr. Jack Uetrecht, Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2. E-mail: jack.uetrecht{at}utoronto.ca

  • This work was supported by Medical Research Council of Canada Grant MT-13478. I.G. was supported by a postdoctoral fellowship from the Pharmaceutical Manufacturers Association of Canada and the Medical Research Council of Canada; G.L. was supported by a postgraduate studentship from the Pharmaceutical Manufacturers Association of Canada and the Medical Research Council of Canada.

  • Abbreviations used are::
    MPO
    myeloperoxidase
    CAD
    collision-activated dissociation
    DMSO
    dimethyl sulfoxide
    KLH
    keyhole limpet hemocyanin
    LC/MS
    liquid chromatography interfaced with mass spectrometry
    LC/MS/MS
    liquid chromatography interfaced with tandem mass spectrometry
    NAC
    N-acetyl-l-cysteine
    PMA
    phorbol 12-myristate-13-acetate
    PAGE
    polyacrylamide gel electrophoresis
    SIM
    selective ion monitoring
    • Received August 27, 1999.
    • Accepted November 9, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (3)
Drug Metabolism and Disposition
Vol. 28, Issue 3
1 Mar 2000
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Research ArticleArticle

Bioactivation and Covalent Binding of Hydroxyfluperlapine in Human Neutrophils: Implications for Fluperlapine-Induced Agranulocytosis

W. George Lai, Iain Gardner, Nasir Zahid and Jack P. Uetrecht
Drug Metabolism and Disposition March 1, 2000, 28 (3) 255-263;

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Research ArticleArticle

Bioactivation and Covalent Binding of Hydroxyfluperlapine in Human Neutrophils: Implications for Fluperlapine-Induced Agranulocytosis

W. George Lai, Iain Gardner, Nasir Zahid and Jack P. Uetrecht
Drug Metabolism and Disposition March 1, 2000, 28 (3) 255-263;
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