Effects of dosing time and schedule on cisplatin-induced nephrotoxicity in rats.

Renal dysfunction induced by a single injection of cisplatin depends on the timing of the dose. However, the effects of repeated administration of cisplatin on time-dependent toxicity have not been evaluated despite the fact that in clinical practice high doses are repeatedly injected at intervals or low doses are administered daily. We studied chrononephrotoxicity in rats after weekly or daily cisplatin injections. Weekly high doses (5 mg kg(-1)) or daily low doses (1.2 mg kg(-1)) of cisplatin were injected at four time points (3, 9, 15 and 21 h after the light was turned on (HALO)) for 3 weeks. Changes in body weight after weekly cisplatin administration were independent of the timing of the doses. In the group that received daily cisplatin, the loss in body weight in the 3 HALO group was smaller than in animals receiving injections at 15 and 21 HALO (P < 0.05 and 0.001, respectively). The blood urea nitrogen and serum creatinine levels in the control rats showed a significant circadian change (peak at 15 HALO and trough at 9 HALO), but these parameters were markedly elevated in both trials and their circadian variations were disturbed. In conclusion, cisplatin-induced nephrotoxicity was the lowest at 3HALO compared with other time points of both dose regimens.