Kinetics of Cisplatin and Its Monohydrated Complex with Sulfur-Containing Compounds Designed for Local Otoprotective Administration

Abstract

The anticancer drug cisplatin can cause permanent inner ear damage. We have determined the second-order degradation rate constant, k_NU, of cisplatin and its more toxic monohydrated complex (MHC) in the presence of each of the sulfur-containing nucleophiles N-acetyl-l-cysteine, l-cysteine methyl ester, 1,3-dimethyl-2-thiourea, d-methionine, and thiosulfate, compounds that are under evaluation for local administration to prevent cisplatin-induced ototoxicity. MHC was isolated from a hydrolysis solution of cisplatin using liquid chromatography (LC). The degradations were evaluated by measuring the disappearance of MHC and cisplatin at 37°C and pH 7.4 in the presence of each of the nucleophiles using LC and photometric detection. The k_NU of MHC and of cisplatin was 0.044 M ¹sec ¹ and 0.012 M ¹sec ¹ with N-acetyl-l-cysteine, 0.24 M ¹sec ¹ and 0.067 M ¹sec ¹ with l-cysteine methyl ester, 0.16 M ¹sec ¹ and 0.074 M ¹sec ¹ with 1,3-dimethyl-2-thiourea, 0.070 M ¹sec ¹ and 0.069 M ¹sec ¹ with d-methionine, and 3.9 M ¹sec ¹ and 0.091 M ¹sec ¹ with thiosulfate, respectively. Our results suggest that thiosulfate, as being the strongest nucleophile, is a promising candidate for local application in order to reduce the inner ear content of MHC and cisplatin. However, otoprotection is a multifactorial event, and it remains to be established how important nucleophilicity is for the effectiveness of the protecting agent.