Use of a toxicity factor to explain differences in nephrotoxicity and myelosuppression among the platinum antitumour derivatives cisplatin, carboplatin and nedaplatin in rats

Abstract

Abstract The platinum antitumour drugs cisplatin, carboplatin and nedaplatin differ in their toxicity. The relationships between the pharmacokinetics of these drugs and developed parameters for predicting their nephrotoxicity and myelosuppression were investigated. The drugs were administered to male Wistar rats by intravenous bolus or infusion, and linearity of pharmacokinetics, total clearance and the apparent ratio of tissue concentrations of unchanged drug to plasma concentration (Kpapp) at steady state were determined. Apparent hydrolysis rates of each drug were determined in-vitro. Nephrotoxicity and myelosuppression were estimated by blood urea nitrogen (BUN) and platelet count, respectively. Tissue exposure to platinum was estimated as the product of the area under the plasma concentration-time curve for unchanged drug (AUCp), Kpapp and the apparent hydrolysis rate constant (khydrolysis), and toxicity factor was defined as the product of Kpapp × khydrolysis as an intrinsic drug parameter. The relationship between AUCp × toxicity factor and BUN fitted well to an Emax model. In bone marrow, this function was also correlated with platelet count. In summary, the product of AUCp × toxicity factor is a factor determining the pharmacokinetics of platinum drug-induced nephrotoxicity and myelosuppression in rats, and this toxicity factor may be a useful parameter for predicting the degree of toxicity of platinum antitumour compounds.