Chronotoxicity of methotrexate in mice and its relation to circadian rhythm of DNA synthesis and pharmacokinetics

Shigehiro Ohdo, Kouichi Inoue, Eiji Yukawa, Shun Higuchi, Shigeyuki Nakano, Nobuya Ogawa

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)283-290
Number of pages8
JournalJapanese Journal of Pharmacology
Volume75
Issue number3
DOIs
Publication statusPublished - Jan 1 1997

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Circadian Rhythm
Methotrexate
Pharmacokinetics
DNA
Light
Leukopenia
Pharmaceutical Preparations
Weight Loss
Body Weight
Inbred ICR Mouse
Tetrahydrofolate Dehydrogenase
Photoperiod
Intraperitoneal Injections
Folic Acid
Bone Marrow Cells
Food
Water

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Chronotoxicity of methotrexate in mice and its relation to circadian rhythm of DNA synthesis and pharmacokinetics. / Ohdo, Shigehiro; Inoue, Kouichi; Yukawa, Eiji; Higuchi, Shun; Nakano, Shigeyuki; Ogawa, Nobuya.

In: Japanese Journal of Pharmacology, Vol. 75, No. 3, 01.01.1997, p. 283-290.

Research output: Contribution to journalArticle

Ohdo, Shigehiro ; Inoue, Kouichi ; Yukawa, Eiji ; Higuchi, Shun ; Nakano, Shigeyuki ; Ogawa, Nobuya. / Chronotoxicity of methotrexate in mice and its relation to circadian rhythm of DNA synthesis and pharmacokinetics. In: Japanese Journal of Pharmacology. 1997 ; Vol. 75, No. 3. pp. 283-290.
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