Cisplatin urinary pharmacokinetics and nephrotoxicity: a common circadian mechanism

Abstract

Renal toxicity and urinary pharmacokinetics following a nonlethal dose (5 mg/kg) of cisplatin were investigated in female F344 (Fischer) rats that were on a standardized light-dark schedule, with water freely available. Circadian timing of drug administration had a major effect on the BUN increase (P less than 0.01), the urine volume increase (P less than 0.025), and the urinary concentration of cisplatin following drug administration (P less than 0.01). Renal toxicity was positively correlated with the peak urinary concentration of cisplatin and with the area under the curve of urinary concentration over the first 20 hours after drug administration (P less than 0.01). Drug administration near the normal circadian maximum of urinary volume prior to treatment resulted in the least renal toxicity, lowest peak, and smallest area of urinary concentration of cisplatin.