Reaction kinetics of cisplatin and its monoaquated species with the modulating agents (di)mesna and thiosulphate

Abstract

The reactive and rapidly excreted thiol mesna (2-mercaptoethane-sulphonate sodium) has the potential to reduce the dose-limiting nephrotoxicity of cisplatin by chemical neutralisation of the latter in the kidney. The reaction kinetics of cisplatin with mesna and its disulphide, dimesna, was studied at 37°C in unbuffered 0.15 mol/l NaCl (pH 5.3) and in 0.15 mol/l NaCl buffered with 0.02 mol/l Hepes (pH 7.4). The reaction mixtures were analysed for intact cisplatin. In the presence of mesna or dimesna 0.5 mol/l as anticipated in urine for conditions of renal protection, the half-life ( t 1 2 ) of 0.2 mmol/l cisplatin was less than 6 min. t 1 2 of 151 and 629 min were found in the presence of mesna and dimesna concentrations of 5 mmol/l and 3 mmol/l, respectively, anticipated in plasma under conditions of renal protection. Cis-diamminemonoaquamonochloroplatinum(II) 0.2 mmol/l reacted rapidly with 50 mmol thiosulphate and 0.5 mol/l (di)mesna ( t 1 2 ⩽ 1 min ). This platinum species also reacted rapidly with 2.6 mmol/l thiosulphate ( t 1 2 < 1 min ), a concentration reached in plasma for conditions under renal protection. Reaction of the monoaquated form of cisplatin proceeded slowly in the presence of dimesna or mesna concentrations (< 5 mmol/l), as anticipated in plasma under renal protecting conditions. It is hypothesised that renal protection by the strong nucleophiles, thiosulphate, mesna and dimesna occurs rather by neutralisation of the aquated species in the lumen of the renal tubulus than by neutralisation of intact cisplatin, and that neutralisation of these species in plasma contributes significantly to the protecting effect.