Pharmacokinetics and toxicodynamics of cisplatin and its metabolites in rats: Relationship between renal handling and nephrotoxicity of cisplatin

The renal handling of cisplatin and its metabolites and the relationship be tween the pharmacokinetics of these platinum species in the kidney and neph rotoxicity in rats were studied by carrying out pharmacokinetic-pharmacodyn amic analysis. Rats received cisplatin intravenously as a bolus (2-10 mg kg(-1)) or by con stant infusion (55 and 140 mug min(-1) kg(-1)). After intravenous administr ation of each platinum species, the platinum concentrations of unchanged ci splatin and its mobile and fixed metabolites were determined separately. Ne phrotoxicity was estimated by measuring the blood urea nitrogen (BUN) level s and the sigmoid Emax model was used to determine the relationship between pharmacokinetic parameters and BUN levels 5 days after cisplatin administr ation. 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 li ver (less than 1 mL(g tissue)(-1)). Concomitant administration of mobile me tabolites did not significantly alter the disposition of cisplatin. Nephrot oxicity, estimated by measuring BUN levels, appeared to be related to the p lasma concentration of intact cisplatin, not total platinum, because mobile metabolites formed from cisplatin showed little nephrotoxicity. The sigmoi d Emax model showed the maximum BUN level reached after cisplatin administr ation was related to the area under the renal cisplatin concentration-time curve (AUCk).