Time-dependent nephrotoxicity associated with daily administration of cisplatin in mice

The chronopharmacokinetics and chronopharmacodynamics of cisplatin were stu died in a mouse model to reveal the mechanisms of dosing time-dependent nep hrotoxicity induced by daily administration. Chronotoxicity was tested by d aily intraperitoneal injections of cisplatin (6 mg kg(-1)) for 5 days at fo ur time points (04 00, 10 00, 16 00 and 22 00 h) in BALB/c mice (n = 6 in e ach group). After following the changes in body weight, serum concentration s of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compar ed. The results showed diurnal variations in cisplatin toxicity, with the 04 00 and 16 00 h time points the best and the worst, respectively, We then meas ured platinum concentrations in blood, liver and kidney and compared the re sults of the 04 00 and 16 00 h groups (n = 4 in each group). Kidney sensiti vity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a m easurement system of interleukin-6 (IL-6) production) between the 04 00 and the 16 00 h groups (n = 4 in each group). These results showed no signific ant difference in platinum accumulation between the two groups. IL-6 produc tion was higher in the 16 00 h group than in the 04 00 h group after saline injection alone (P < 0.05). Cisplatin treatment alone did not increase IL- 6 production. However, IL-6 levels were markedly augmented by cisplatin wit h LPS. In conclusion, chrononephrotoxicity induced by daily cisplatin administrati on does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.