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Research ArticleArticle

Kinetic Analysis of the Reactions of 4-Hydroperoxycyclophosphamide and Acrolein With Glutathione, Mesna, and Wr-1065

Kirk A. Tacka, James C. Dabrowiak, Jerry Goodisman and Abdul-Kader Souid
Drug Metabolism and Disposition August 2002, 30 (8) 875-882; DOI: https://doi.org/10.1124/dmd.30.8.875
Kirk A. Tacka
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James C. Dabrowiak
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Jerry Goodisman
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Abdul-Kader Souid
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Abstract

The kinetics of the reactions of glutathione (GSH) with 4-hydroperoxycyclophosphamide (4OOH-CP) and acrolein, a metabolite of 4OOH-CP, were investigated in a cell-free medium (pH ∼7.5) and peripheral blood mononuclear cells. The ability of the thiol drugs, sodium 2-mercaptoethane sulfonate (mesna) andS-2-(3-aminopropylamino)ethanethiol (WR-1065), to affect the reactions of cellular GSH with the alkyalting agents was also studied. The amount of unreacted thiols in the various reactions was determined by derivatization with monobromobimane, followed by separation of fluorescent-labeled thioether adducts using high-pressure liquid chromatography. The second-order rate constants (k2) for reactions of GSH, mesna, and WR-1065 with 4OOH-CP in solution were 38 ± 5, 25 ± 5, and 880 ± 50 M−1s−1, respectively. The corresponding k2 for reactions of GSH, mesna, and WR-1065 with acrolein were 490 ± 100, 700 ± 150, and >2000 M−1s−1, respectively. The apparent rate constants for reactions of cellular GSH with acrolein and 4OOH-CP were smaller than those obtained in solution. Assuming that thek2 is the same inside and outside cells, we estimate the first-order rate constant (k1) for transfer of 4OOH-CP and acrolein across the cell membrane as ∼0.01 and ∼0.04 s−1, respectively. WR-1065 was more effective than mesna in blocking depletion of cellular GSH (because it passes into the cell more quickly and has higher reaction rates with the alkylators than the latter compound). When WR-1065 and mesna were used together, the protection against cellular depletion of GSH was additive. Our results are relevant to the administration of thiol drugs with high-dose alkylating agents.

Footnotes

  • This work was submitted in partial fulfillment of the requirements for a Ph.D. degree for K. A. T. in the Biochemistry, Structural Biology and Biophysics Program at Syracuse University.

  • Abbreviations used are::
    GSH
    glutathione
    4OOH-CP
    4-hydroperoxycyclophosphamide
    mesna
    sodium 2-mercaptoethanesulfonate
    WR-2721
    (amifostine),S-2-(3-aminopropylamino)ethyl phosphorothioic acid
    WR-1065
    S-2-(3-aminopropylamino)ethanethiol
    PBMC
    peripheral blood mononuclear cells
    MSA
    methanesulfonic acid
    mBBr
    monobromobimane
    DTNB
    5,5′-dithio-bis(2-nitrobenzoic acid)
    HPLC
    high-pressure liquid chromatography
    RSH
    (GSH, mesna, or WR-1065)
    A
    alkylator (4OOH-CP, acrolein, or mBBr)
    k1
    pseudo-first-order rate constant
    k2
    second-order rate constant
    RT
    room temperature
    • Received January 31, 2002.
    • Accepted April 26, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (8)
Drug Metabolism and Disposition
Vol. 30, Issue 8
1 Aug 2002
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Research ArticleArticle

Kinetic Analysis of the Reactions of 4-Hydroperoxycyclophosphamide and Acrolein With Glutathione, Mesna, and Wr-1065

Kirk A. Tacka, James C. Dabrowiak, Jerry Goodisman and Abdul-Kader Souid
Drug Metabolism and Disposition August 1, 2002, 30 (8) 875-882; DOI: https://doi.org/10.1124/dmd.30.8.875

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Research ArticleArticle

Kinetic Analysis of the Reactions of 4-Hydroperoxycyclophosphamide and Acrolein With Glutathione, Mesna, and Wr-1065

Kirk A. Tacka, James C. Dabrowiak, Jerry Goodisman and Abdul-Kader Souid
Drug Metabolism and Disposition August 1, 2002, 30 (8) 875-882; DOI: https://doi.org/10.1124/dmd.30.8.875
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