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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Kinetic Study on the Reactions of Platinum Drugs with Glutathione

Douglas Hagrman, Jerry Goodisman and Abdul-Kader Souid
Journal of Pharmacology and Experimental Therapeutics February 2004, 308 (2) 658-666; DOI: https://doi.org/10.1124/jpet.103.059410
Douglas Hagrman
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Jerry Goodisman
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Abdul-Kader Souid
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Abstract

The binding of platinum (Pt) drugs (oxaliplatin, carboplatin, and cisplatin) to glutathione (GSH, 6.75 mM) was investigated at 37°C in Hepes (100 mM, pH ∼7.4) or Tris-NO3 (60 mM, pH 7.4) buffer and NaCl (4.62, 6.63, or 7.82 mM). The conditions were chosen to mimic passage of clinical concentrations of the drugs (135 μM) through the cytosol. The reactions were monitored by UV-absorption spectroscopy, high-performance liquid chromatography (HPLC), and atomic absorption spectroscopy. The initial rates, detected by UV absorbance, were similar for oxaliplatin and cisplatin reacting with GSH and were more than 5-fold faster than for carboplatin reacting with GSH. The Pt contents in HPLC eluates corresponding to unbound drug decreased exponentially with time, confirming that the reactions were first order in [Pt drug] and allowing determination of the pseudo first-order rate constants (k1). The second-order rate constants (k2) were calculated as k1 divided by [GSH]. The k2 value for oxaliplatin reacting with GSH was ∼3.8 × 10–2 M–1 s–1, for cisplatin reacting with GSH ∼2.7 × 10–2 M–1 s–1, and for carboplatin reacting with GSH ∼1.2 × 10–3 M–1 s–1 (∼32-fold slower than that of oxaliplatin and ∼23-fold slower than that of cisplatin). These results demonstrate an influence of ligands surrounding the Pt coordination sphere on the reactivity of Pt2+ with GSH.

Footnotes

  • This work was supported by a generous fund from the Paige's Butterfly Run.

  • DOI: 10.1124/jpet.103.059410.

  • ABBREVIATIONS: GSH, glutathione; HPLC, high-performance liquid chromatography; tR, retention time; k1, pseudo first-order rate constant; k2, second-order rate constant; Pt, platinum; AAS, atomic absorption spectroscopy; dH2O, distilled deionized water; Pt-SG, Pt-sulfur product.

    • Received August 31, 2003.
    • Accepted October 29, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 2
1 Feb 2004
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Kinetic Study on the Reactions of Platinum Drugs with Glutathione

Douglas Hagrman, Jerry Goodisman and Abdul-Kader Souid
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 658-666; DOI: https://doi.org/10.1124/jpet.103.059410

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Kinetic Study on the Reactions of Platinum Drugs with Glutathione

Douglas Hagrman, Jerry Goodisman and Abdul-Kader Souid
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 658-666; DOI: https://doi.org/10.1124/jpet.103.059410
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