摘要 : 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 su... 展开 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 degrees 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(-1)sec(-1) and 0.012 M(-1)sec(-1) with N-acetyl-l-cysteine, 0.24 M(-1)sec(-1) and 0.067 M(-1)sec(-1) with l-cysteine methyl ester, 0.16 M(-1)sec(-1) and 0.074 M(-1)sec(-1) with 1,3-dimethyl-2-thiourea, 0.070 M(-1)sec(-1) and 0.069 M(-1)sec(-1) with d-methionine, and 3.9 M(-1)sec(-1) and 0.091 M(-1)sec(-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. 收起