Chronotoxicity and Chronopharmacokinetics of Methotrexate in Mice: Modification by Feeding Schedule

The Japanese Journal of Pharmacology

Nobuya Ogawa²  Shigeyuki Nakano¹  Jian Guo Song²  Shigehiro Ohdo² 

[1] Department of Clinical Pharmacology and Therapeutics, Oita Medical University;Department of Pharmacology, Ehime University School of Medicine

关键词: Methotrexate;    Chronotoxicity;    Chronopharmacokinetics;    Circadian rhythm;    Feeding schedule;   

DOI  :  10.1254/jjp.62.373

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(30)Cited-By(8)The circadian rhythms of the toxicity and the pharmacokinetics of methotrexate (MTX), as well as the effects of manipulation of feeding schedule on the rhythms, were investigated in mice. Male ICR mice were housed under a standardized light-dark cycle (12:12) with food and water ad libitum (ALF) or under the time-restricted feeding (TRF) schedule (8 hr during the light phase) for 1 day or 14 days before the drug administration. The animals received MTX (100 mg/kg, i.p.) once daily for 7 days in the toxicity studies and a single dose of MTX (100 mg/kg, i.p.) for the kinetic studies. Under the ALF, a significant dosing time dependency was demonstrated for the toxicity of MTX with a longer survival time for the middark dosing and a shorter one for the midlight dosing. The MTX kinetics also showed a significant rhythm, with the highest clearance at middark and the lowest one at midlight. The rhythm in MTX kinetics well coincided with that in the toxicity of the drug. The TRF had a marked influence on the rhythms of MTX kinetics and toxicity. Thus, the timing of dosing is important in the kinetics and the toxicity of MTX in mice, and the manipulation of feeding schedule can modify the rhythm of the toxicity by changing that of the MTX kinetics.

【 授权许可】

Unknown