Dosing-time contributes to chronotoxicity of clofarabine in mice via means other than pharmacokinetics.
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.
Institute of Clinical Pharmacy, Wannan Medical College, Wuhu, China; Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, China.
Jia-Jie
JJ
Luan
Institute of Clinical Pharmacy, Wannan Medical College, Wuhu, China; Department of Pharmacy, Chinese People's Liberation Army 150th Central Hospital, Luoyang, China.
Yu-Shan
YS
Zhang
Institute of Clinical Pharmacy, Wannan Medical College, Wuhu, China; Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, China.
Xiao-Yun
XY
Liu
Institute of Clinical Pharmacy, Wannan Medical College, Wuhu, China.
Ya-Qin
YQ
Wang
Institute of Clinical Pharmacy, Wannan Medical College, Wuhu, China; Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, China.
Jian
J
Zuo
Institute of Clinical Pharmacy, Wannan Medical College, Wuhu, China. Electronic address: cpyjsyy@126.com.
Jian-Guo
JG
Song
Institute of Clinical Pharmacy, Wannan Medical College, Wuhu, China; Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, China.
Wen
W
Zhang
Institute of Clinical Pharmacy, Wannan Medical College, Wuhu, China.
Wu-San
WS
Wang
D000227:Adenine Nucleotides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D001087:Arabinonucleosides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects; D000077866:Clofarabine; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D013997:Time Factors; D023382:Toxicity Tests, Acute
D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D000077866:Clofarabine
Circadian rhythm; Clofarabine; Pharmacokinetics; Toxicity