Shigehiro Ohdo (1), Kouichi Inoue (1), Eiji Yukawa (1), Shun Higuchi
(1), Shigeyuki Nakano (2) and Nobuya Ogawa (3)
(1) Department of Clinical Pharmacokinetics, Division of Pharmaceutical
Science, Kyushu University, Fukuoka 812, Japan
(2) Department of Clinical Pharmacology and Therapeutics, Oita Medical University,
Oita 879-55, Japan
(3) Department of Pharmacology, Ehime University School of Medicine, Ehime
791-02, Japan
Abstract: The mechanisms underlying the circadian rhythm of methotrexate
(MTX-induced toxicity (body weight loss and leukopenia) were investigated
from the viewpoints of the sensitivity of living organisms to the drug and
the pharmacokinetics of the drug. ICR male mice were housed in a standardized
light-dark cycle (lights on at 0700, off at 1900) with food and water ad
libitum. The body weight loss after an intraperitoneal injection of MTX
(400 mg/kg) was more serious in the late dark period and 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 period. Lower toxicity was observed
when DNA synthesis, dihydrofolate reductase (DHFR) activity in bone marrow
cells and folate level in plasma decreased, and higher toxicity was observed
when they increased. There was a significant circadian rhythm in plasma
MTX concentration, with a higher level in the light period and a lower level
in the dark period. The circadian rhythm of plasma MTX concentration was
associated with that of MTX-induced toxicity. The present study suggests
that the circadian rhythm of MTX-induced toxicity is caused by that of the
sensitivity of living organisms to the drug and the pharmacokinetics of
the drug.
Keywords: Methotrexate, Chronotoxicity, Chronopharmacokinetics, Cell
cycle, Circadian rhythm