Lethal nephrotoxicity and hematologic toxicity of cis-diamminedichloroplatinum ameliorated by optimal circadian...

Three hundred and forty-one female F344 (Fischer) rats were kept in light for 8 hr alternating with darkness for 16 hr; some were observed for survival for 21 days, while others were killed for blood sampling 4.5 days after a single intraperitoneal (i.p.) injection of 11 mg/kg cis-diamminedichloroplatinum (cis-DDP). cis-DDP was administered with or without concomitant i.p. saline load at one of six equispaced circadian stages. This high dose of cis-DDP resulted in marked lethal and renal toxicity, but in a moderate bone marrow suppression. Blood urea nitrogen (BUN), circulating total white blood cell counts (WBC) and survival times revealed statistically significant circadian rhythms of drug toxicity (P less than 0.03). Optimal tolerance for cis-DDP gauged by these three variables resulted from drug administration in the second half of the dark span. Renal tolerance for cis-DDP guaged by BUN was improved two-fold by appropriate drug timing. This benefit from drug timing alone was further improved two-fold if hydration and cis-DDP were given at the optimal circadian stage. Hydration-induced ameloriation of cis-DDP nephrotoxicity requires time qualification of both hydration and cis-DDP.