Kinetic Study on the Reactions of Platinum Drugs with Glutathione

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antineoplastic agent; buffer; carboplatin; cisplatin; glutathione; ligand; oxaliplatin; platinum; platinum complex; platinum derivative; sodium chloride; article; atomic absorption spectrometry; calculation; chemistry; cytosol; drug binding; high performance liquid chromatography; kinetics; pH; pharmacokinetics; priority journal; radiation absorption; time; ultraviolet radiation; ultraviolet spectrophotometry




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.

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Copyright 2003 The Journal of Pharmacology and Experimental Therapeutics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and The Journal of Pharmacology and Experimental Therapeutics.

The article may be found at DOI: 10.1124/jpet.103.059410.


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