The chemical reactivity of the modulating agent WR2721 (ethiofos) and its main metabolites with the antitumor agents cisplatin and carboplatin

Abstract The antitumor agents cisplatin [ cis -diamminedichloroplatinum(II), CDDP] and carboplatin [ cis -diammine(1,1-cyclobutanedicarboxylato)platinum(II), CBDCA] can react with a nucleophilic agent by a direct ligand exchange of the (labile) anionic ligands or through hydrolysis of these ligands followed by a fast reaction of the hydration product with the nucleophile. At pH 7.4 and 37°, CDDP and CBDCA were incubated with several molar excesses of the modulating agent WR2721, its active thiol metabolite WR1065 or the symmetrical disulphide WR33278. The reaction rate constants for the hydrolysis and the direct inactivation by the WR-compounds were obtained from the pseudo first-order disappearance of the intact Pt-drug, with or without the WR-compounds at molar ratios of 50,100 and 200. The hydrolysis of carboplatin ( k aq,CBDCA = 2 × 10 −8 M −1 sec −1 ) was 100-fold less rapid than that of cisplatin ( k aq,CDDP = 2 × 10 −6 M −1 sec −1 ). However, direct inactivation by WR2721, WR1065 and WR33278 was only 4-, 4- and 22-fold less rapid for carboplatin than for cisplatin, respectively. This direct inactivation was slow compared to the strong nucleophiles thiosulphate (TS) and diethyldithiocarbamate (DDTC) and decreased for both Pt-drugs in the following order: WR1065 ( k WR1065/CDDP = 49.1 × 10 −4 M −1 sec −1 , k WR1065/CBDCA = 12.4 × 10 −4 M −1 sec −1 ) > WR2721 ( k WR2721/CDDP = 25.3 × 10 −4 M −1 sec −1 , k WR2721/CBDCA = 6.07 × 10 −4 M −1 sec −1 ) > WR33278 ( k WR33278/CDDP = 8.60 × 10 −4 M −1 sec −1 , k WR33278/CBDCA = 0.39 × 10 −4 M −1 sec −1 ). Thus for CDDP, the hydrolysis-mediated interaction with the WR-compounds contributed more to the disappearance of intact platinum antitumor agent than it did for CBDCA. Considering the relatively low reactivity of WR2721 and its main metabolites with the platinum antitumor agents, in addition to their pharmacokinetic behavior, a significant inactivation of the plantinum antitumor drugs by WR2721 and its main metabolites is, in contrast to TS, not expected in the circulation.