Pharmacokinetic–Pharmacodynamic Analysis of Cisplatin with Hydration and Mannitol Diuresis: The Contribution of Urine Cisplatin Concentration to Nephrotoxicity

Background and ObjectivesForced diuresis, high-volume hydration with diuresis, is widely used as a prophylactic treatment against cisplatin nephrotoxicity. However, the details of the underlying mechanisms and the optimal protocol of forced diuresis remain unclear. The present study investigated the alterations in pharmacokinetics and pharmacodynamics (nephrotoxicity) of cisplatin with forced diuresis treatment.MethodsCisplatin (5 mg/kg) was intravenously injected to rats (5 rats/group, except for control group in pharmacodynamic study, n = 13) treated with or without forced diuresis 2-h pre- and post-hydration with 10% mannitol at different infusion rates (0.3, 1.0, and 3.0 mL/h). The unbound cisplatin concentrations in plasma and urine, and the platinum amount in the kidney were monitored in the pharmacokinetic studies. The plasma creatinine concentration was evaluated as an index of nephrotoxicity in the pharmacodynamic studies.ResultsForced diuresis treatment did not significantly alter the plasma cisplatin pharmacokinetics but dramatically decreased the urine concentration of unbound cisplatin and its accumulation into the kidneys in a dose-dependent manner, and correspondingly, nephrotoxicity was dose-dependently attenuated by forced diuresis. The pharmacokinetic–pharmacodynamic analysis suggested that the urine cisplatin concentration has a comparable impact on the cisplatin-induced nephrotoxicity to that in plasma, probably owing to the reabsorption of cisplatin from urine, which can be attenuated by forced diuresis.ConclusionsThese results indicated that the nephroprotective effect of forced diuresis is a pharmacokinetic-based drug–drug interaction possibly due to the inhibition of cisplatin reabsorption from urine. Monitoring of urine cisplatin concentration may lead to the optimization of a forced diuresis protocol with mannitol.