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 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 (