Kinetic Study on the Reactions of Platinum Drugs with Glutathione

Douglas Hagrman, Jerry Goodisman, Abdul Kader Souid

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)658-666
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume308
Issue number2
DOIs
Publication statusPublished - Feb 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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