Pharmacokinetics and Toxicodynamics of Cisplatin and Its Metabolites in Rats: Relationship between Renal Handling and Nephrotoxicity of Cisplatin

Abstract

Abstract The renal handling of cisplatin and its metabolites and the relationship between the pharmacokinetics of these platinum species in the kidney and nephrotoxicity in rats were studied by carrying out pharmacokinetic-pharmacodynamic analysis. Rats received cisplatin intravenously as a bolus (2–10 mgkg−1) or by constant infusion (55 and 140 μg min−1 kg−1). After intravenous administration of each platinum species, the platinum concentrations of unchanged cisplatin and its mobile and fixed metabolites were determined separately. Nephrotoxicity was estimated by measuring the blood urea nitrogen (BUN) levels and the sigmoid Emax model was used to determine the relationship between pharmacokinetic parameters and BUN levels 5 days after cisplatin administration. Cisplatin and its mobile metabolites in plasma distributed more rapidly and extensively into the kidney (mean apparent kidney-to-plasma concentration ratios were 2.69 and 7.12 mL (g tissue)−1, respectively) than into the liver (less than 1 mL (g tissue)−1). Concomitant administration of mobile metabolites did not significantly alter the disposition of cisplatin. Nephrotoxicity, estimated by measuring BUN levels, appeared to be related to the plasma concentration of intact cisplatin, not total platinum, because mobile metabolites formed from cisplatin showed little nephrotoxicity. The sigmoid Emax model showed the maximum BUN level reached after cisplatin administration was related to the area under the renal cisplatin concentration-time curve (AUCk).