Dosing‐time contributes to chronotoxicity of clofarabine in mice via means other than pharmacokinetics

Abstract

To evaluate the time- and dose-dependent toxicity of clofarabine in mice and to further define the chronotherapy strategy of it in leukemia, we compared the mortality rates, LD50s, biochemical parameters, histological changes and organ indexes of mice treated with clofarabine at various doses and time points. Plasma clofarabine levels and pharmacokinetic parameters were monitored continuously for up to 8 hours after the single intravenous administration of 20 mg/kg at 12:00 noon and 12:00 midnight by high performance liquid chromatography (HPLC)-UV method. Clofarabine toxicity in all groups fluctuated in accordance with circadian rhythms in vivo. The toxicity of clofarabine in mice in the rest phase was more severe than the active one, indicated by more severe liver damage, immunodepression, higher mortality rate, and lower LD50. No significant pharmacokinetic parameter changes were observed between the night and daytime treatment groups. These findings suggest the dosing-time dependent toxicity of clofarabine synchronizes with the circadian rhythm of mice, which might provide new therapeutic strategies in further clinical application.

Molecular Aspects of Circadian Pharmacology and Relevance for Cancer Chronotherapy

“…In a recently performed chronopharmacological study, a second generation nucleotide analogue clofarabine which is used for the treatment of hematological malignancies such as acute leukemia was administered to mice, and time- and dose-dependent toxicity was evaluated by examining biochemical parameters, histological changes, and organ indexes of mice. Clofarabine toxicity in mice when administered in the rest phase was more severe than the active phase, demonstrated by more severe liver damage, immunosuppression, higher mortality rate, and lower LD50 [ 173 ].…”