Modification of the physicochemical and pharmacological properties of anticancer platinum compounds by commercial 5-fluorouracil formulations: a comparative study using cisplatin and carboplatin

Abstract

The influence of a commercial formulation of 5-fluorouracil (5-FU) on the stability and pharmacological properties of two platinum derivatives, cisplatin and carboplatin, was studied to determine whether the drugs could be mixed in containers or intravenous lines. When cisplatin was incubated in a French commercial formulation of 5-FU (Fluoro-uracile, Roche, France), high-performance liquid chromatographic (HPLC) studies demonstrated a rapid disappearance of the parent platinum compound, the extent of the degradation being 75% after 3.5 h. These studies also revealed that the degradation was not caused by a reaction between 5-FU and cisplatin but rather resulted from an interaction between cisplatin and trometamol, the excipient used in the French 5-FU formulation to buffer the solution at pH 8.2. The sole presence of trometamol in a cisplatin solution for 24 h at 30 degrees C resulted in the complete inhibition of both the ability of cisplatin to bind in vitro to human serum albumin and the antitumor activity of the cytostatic agent against P388 leukemia in mice (T/C% = 88% for cisplatin+trometamol vs greater than 333% for cisplatin). When cisplatin was incubated at the same pH in trometamol-free sodium hydroxide solutions (the excipient used in 5-FU formulations in several countries, including the United States and the United Kingdom), the parent compound was transformed into reactive species that were toxic to mice (T/C% = 40% in P388 leukemia). The degradation determined for a carboplatin-trometamol admixture using HPLC was similar to that found for cisplatin but occurred at a slower rate (0 after 3.5 h incubation and 55% after 24 h). The antitumor activity of carboplatin in P388-bearing mice was not significantly altered by a 24-h period of preincubation in the presence of trometamol (T/C% = 209% vs 241% for treatment with carboplatin in the absence of trometamol). As in the case of cisplatin, incubation of carboplatin for 24 h in a sodium hydroxide solution resulted in a toxic effect (T/C% = 64%). Our results thus demonstrate the incompatibility of both cisplatin and carboplatin with commercial formulations of 5-FU.