Kinetics of Cisplatin and its monohydrated complex with sulfur-containing compounds designed for local otoprotective administration.
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.
Videhult
Pernilla
P
Karolinska Pharmacy, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. pernilla.videhult@apoteket.se
Laurell
Göran
G
Wallin
Inger
I
Ehrsson
Hans
H
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D002853:Chromatography, Liquid; D002945:Cisplatin / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D007758:Ear, Inner / Q000187:drug effects* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D012044:Regression Analysis; D013457:Sulfur Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D013696:Temperature; D013885:Thiosulfates / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity
D000970:Antineoplastic Agents; D013457:Sulfur Compounds; D013885:Thiosulfates; D002945:Cisplatin