Physiological pharmacokinetic modeling of cis-dichlorodiammineplatinum(II) (DDP) in several species

Abstract

A physiological pharmacokinetic analysis of cis-dichlorodiammineplatinum(II) (DDP) is presented for the rabbit, dog, and human. The results are compared to a previous analysis for the rat. DDP binds irreversibly to low-molecular weight nucleophiles and macromolecules to form mobile and fixed metabolites at rates which are tissue-specific. The rate constant for the formation of fixed metabolite in plasma, determined by in vitro incubation, ranges from 0.004 to 0.008 min-1 in all species. Urinary excretion is the major route of platinum elimination in all species, with a kidney clearance of DDP approximating GFR in all species. Biliary clearance accounts for the elimination of 1-5% of dose and was neglected. The tissue-specific DDP-to-protein binding rates are in the order: kidney/skin/liver/gut/muscle for the beagle dog and rat. The rate constants for the rabbit and mongrel dog are similar, except that the skin and liver are reversed. The binding rate constants for various tissues are similar for all species. The rate constants for release of Pt from macromolecules are similar to protein turnover rate constants and decrease with increasing body weight. Human pharmacokinetic behavior was predicted by estimating human parameters by extrapolation of the animal data. The simulations in humans are compared to experimental plasma concentration and urine excretion profiles for several doses and durations of infusion.