CHRONOTOXICITY OF METHOTREXATE IN MICE AND ITS RELATION TO CIRCADIAN-RHYTHM OF DNA-SYNTHESIS AND PHARMACOKINETICS

The mechanisms underlying the circadian rhythm of methotrexate (MTX)-i nduced toxicity (body weight loss and leukopenia) were investigated fr om the viewpoints of the sensitivity of living organisms to the drug a nd the pharmacokinetics of the drug. ICR male mice were housed in a st andardized light-dark cycle (lights on at 0700, off at 1900) with food and water ad libitum. The body weight loss after an intraperitoneal i njection of MTX (400 mg/kg) was more serious in the late dark period a nd the early light period and milder in the late light period and the early dark period. The MTX-induced leukopenia was more serious in the late dark period and the light period and milder in the early dark per iod. Lower toxicity was observed when DNA synthesis, dihydrofolate red uctase (DHFR) activity in bone marrow cells and folate level in plasma decreased, and higher toxicity was observed when they increased. Ther e was a significant circadian rhythm in plasma MTX concentration, with a higher level in the light period and a lower level in the dark peri od. The circadian rhythm of plasma MTX concentration was associated wi th that of MTX-induced toxicity. The present study suggests that the c ircadian rhythm of MTX-induced toxicity is caused by that of the sensi tivity of living organisms to the drug and the pharmacokinetics of the drug.