Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumour activity of cisplatin

Abstract

For rats dosed with cisplatin the rate of appearance in plasma of ultrafilterable metabolites containing platinum has been investigated using HPLC. At least seven species containing platinum in addition to cisplatin are present 15 min following injection i.p. of 15 mg kg −1. Unchanged cisplatin has been almost completely eliminated from the plasma within 3 hr of dosing; however, metabolite species are still present. The same metabolite species form when cisplatin is incubated in vitro with plasma although in different proportions. After incubation for 24 hr at 37% a mixture of metabolites is produced which contains less than 4% cisplatin. This mixture, when injected i.p. into rats, is nephrotoxic at doses of platinum at which cisplatin is not. The mixture of metabolites has considerably less antitumour activity than cisplatin when tested against the mouse L1210 leukemia assay. Although no metabolite species has been unequivocally identified we present evidence which suggests that amongst the principle metabolite species are an hydrolysis product and methionine substitution products of cisplatin. A mixture of cisplatin methionine substitution complexes showed neither antitumour nor nephrotoxic properties. However, an hydrolysis product was shown to be nephrotoxic at a dose of platinum at which cisplatin is not. The work reported here is the first direct experimental demonstration that cisplatin metabolites are more nephrotoxic but less effective antitumour agents than the parent compound.