Experimental and theoretical studies on the chemistry of cisplatin (DDP) have been continued with the goal of characterizing the reaction kinetics of the drug in vitro. Principal reactive species and pathways have been identified over the first 24 hours of drug reaction in various buffered inorganic solutions and plasma ultrafiltrates. The hydrolysis products of DDP in buffered choloride solutions have been measured for 25 hours by HPLC/electrochemical detection techniques over a pH range of 5.5 to 7.8. A kinetic model has been developed that accurately accounts for the concentration-time profiles of both parent drug and monoaquo/monohydroxo derivatives. Furthermore, the rate constant describing the reverse monoaquo to parent DDP reaction has been determined as well as the acid dissociation constant of the monoaquo/monohydroxo species. Extrapolations from this model to the pH and chloride levels found in plasma ultrafiltrate reveal that, while the relatively alkaline pH of plasma (7.4) accounts for a moderate fraction of the observed drug reactivity, pH alone does not account for all reactivity. Hence amino acid and Krebs cycle metabolites normally found in plasma have been investigated for reactivity. Histidine, methionine, and several Krebs cycle metabolites were found to be only weakly reactive or unreactive. Cysteine was found to be more reactive but exact quantitation requires further modification of the HPLC separation/detection method since cysteine/drug products coelute with monoaquo derivatives.
