CHRONOTOXICITY AND CHRONOPHARMACOKINETICS OF METHOTREXATE IN MICE - MODIFICATION BY FEEDING SCHEDULE

The circadian rhythms of the toxicity and the pharmacokinetics of meth otrexate (MTX), as well as the effects of manipulation of feeding sche dule on the rhythms, were investigated in mice. Male ICR mice were hou sed 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 admi nistration. 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 surv ival time for the middark dosing and a shorter one for the midlight do sing. The MTX kinetics also showed a significant rhythm, with the high est clearance at middark and the lowest one at midlight. The rhythm in MTX kinetics well coincided with that in the toxicity of the drug. Th e TRF had a marked influence on the rhythms of MTX kinetics and toxici ty. Thus, the timing of dosing is important in the kinetics and the to xicity of MTX in mice, and the manipulation of feeding schedule can mo dify the rhythm of the toxicity by changing that of the MTX kinetics.