Computational consideration of cisplatin hydrolysis and acid dissociation in aqueous media: effect of total drug concentrations.
Cisplatin (cis-DDP) is subject to nucleophilic displacement of chloride in water, forming aquated species, subsequently liberating hydrogen ion(s) with increasing pH. This study intends to theoretically analyze the hydrolysis and polyprotic dissociation behavior of cis-DDP in various aqueous media. A mathematical model was expressed by nonlinear simultaneous equations in terms of the total drug concentration, pH and pCl based on the hydrolysis and acid dissociation constants already published. Some of the interesting simulation results include that (1) in water, cis-DDP behaves in a very complicated manner, highly depending on the total drug concentration, pH and pCl, (2) in normal saline, about 3% of the total concentration is a positively charged chloro-aqua that may be very reactive, (3) in assumed blood (pH 7.4, [Cl(-)]=0.11 mol/l, mu=0.15), the drug is stabilized at the level of 85% and the remnants are the chloro-hydroxo (11%) and the chloro-aqua (4%), (4) in assumed intracellular conditions (pH 7.1, [Cl(-)]=0.01 mol/l, mu=0.15), the drug is converted to a large extent to various species including the parent species (44%), the chloro-hydroxo (30%), hydroxo-aqua (2%), chloro-aqua (24%) diaqua (less than 1%) and dihydroxo (null). The results of this analysis may provide a useful preliminary knowledge of existing species in a system concerned and a rationale for re-evaluating the reactions between cis-DDP and various nucleophilic substances already reported while there are somewhat conflicting interpretations of some cis-DDP reactions.
Yotsuyanagi
Toshihisa
T
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Japan. yotsuyng@phar.nagoya-cu.ac.jp
Usami
Makiko
M
Noda
Yasuhiro
Y
Nagata
Mariko
M
D000970:Antineoplastic Agents / Q000737:chemistry; D002945:Cisplatin / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008956:Models, Chemical; D012965:Sodium Chloride; D012995:Solubility; D014867:Water
D000970:Antineoplastic Agents; D014867:Water; D012965:Sodium Chloride; D002945:Cisplatin