PT  - JOURNAL ARTICLE
AU  - Douglas Hagrman
AU  - Jerry Goodisman
AU  - Abdul-Kader Souid
TI  - Kinetic Study on the Reactions of Platinum Drugs with Glutathione
AID  - 10.1124/jpet.103.059410
DP  - 2004 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 658--666
VI  - 308
IP  - 2
4099  - http://jpet.aspetjournals.org/content/308/2/658.short
4100  - http://jpet.aspetjournals.org/content/308/2/658.full
SO  - J Pharmacol Exp Ther2004 Feb 01; 308
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics