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ORIGINAL RESEARCH ARTICLE

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

Pernilla Videhult^*,,1, Göran Laurell, Inger Wallin^* and Hans Ehrsson^*,

^* Karolinska Pharmacy, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; and Institute for Hearing and Communications Research, Karolinska Institutet, Stockholm, Sweden

To whom requests for reprints should be addressed at ¹ Karolinska Pharmacy, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: pernilla.videhult{at}apoteket.se

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.

Key Words: antioxidants • cis-diamminedichloroplatinum • hydrated species • nucleophiles • ototoxicity

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