Disposition of Cisplatin vs Total Platinum in Animals and Man

Abstract

Optimal clinical performance of antineoplastic agents is realized by maximizing cytotoxicity toward cancerous elements while limiting drug action on normal tissue. Effectiveness is controlled by the absorption, distribution and excretion characteristics of the drug as well as its biotransformation pattern. Biotransformation is a particularly important consideration in clinical utilization of chemically reactive molecules, such as cisplatin. Such compounds are known to rapidly degrade once in contact with blood components (1). This breakdown apparently results from nucleophilic displacement of chloride ligands by endogenous nucleophiles either directly or through aquatedplatinum intermediates (2). Coordination of platinum with these nucleophiles yields complexes apparently exhibiting different spectra of biological activity and toxicity, and different distribution and excretion characteristics. Thus, a discussion of the clinical pharmacology and pharmacokinetics of cisplatin must be based on quantitative data describing the fate of the individual platinum species differing in ligand composition about the metal as well as an evaluation of the biological activity of these individual biodegradation products. Although the degradation reactions are apparently not enzyme-mediated, general “metabolic” pathways should be definable; the structure of specific reaction products, however, may vary among individuals, being determined by the nature and concentration of potential reactant molecules (those with available nucleophilic centers) which in turn are influenced by a variety of environmental, dietary and health factors. This chapter describes some of the sensitive analytical methodology developed in our laboratories to selectively monitor individual platinum-containing species and the application of that technology to begin to describe the disposition of cisplatin in man in clinically relevant situations and in animals.