Reduction of cis-diamminedichloroplatinum nephrotoxicity in rats by optimal circadian drug timing

Abstract

A prominent circadian rhythm in the nephrotoxicity of a therapeutic dose of cis-diamminedichloroplatinum (cisplatin) is demonstrated in female Fischer rats. Rats were randomized to receive two doses of either cisplatin or 0.9% NaCl solution 14 days apart at the times of either high or low values in their circadian rhythm of urinary volume. Toxicity was assessed by measuring changes in body weight and changes in the 24-hr means of urinary volume, blood urea nitrogen, and urinary beta-N-acetylglucosaminidase (NAG) activity. Toxicity was least in rats which received the drug near the circadian maximum of urinary volume. Conversely, rats which received the same dose of drug near the circadian minimum of urinary volume lost more weight and exhibited a 2-fold increase in the 24-hr mean of urinary volume, a 3-fold rise in the 24-hr mean of blood urea nitrogen, and a 5-fold increase in the 24-hr mean of urinary NAG activity. A positive correlation between urinary NAG at the time of cisplatin administration and the extent of cisplatin nephrotoxicity was demonstrated (p less than 0.02). A correlation also was found between tissue NAG concentration and tissue uptake of cisplatin (p less than 0.001). A marked circadian rhythm of NAG activity in proximal tubular cells may contribute to the prominent circadian rhythm in murine renal tolerance for cisplatin.