Chronotoxicity of Methotrexate in Mice and Its Relation to Circadian Rhythm of DNA Synthesis and Pharmacokinetics

Abstract

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 organ isms 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.

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

“…In previous studies, these doses of methotrexate alone disrupted conditioned taste aversion, conditioned emotional responses, spatial memory, and novel object recognition (Madhyastha et al 2002;Seigers et al 2008;Yanovski et al 1989) but failed to alter responding in a different conditioned taste aversion assay and a Pavlovian appetitive conditioning assay (Stock et al 1995). The doses of 3.2-32 mg/kg methotrexate used in mice and rats fall within the predicted 8-42-mg/kg-scaled mouse doses as determined from the range of clinical doses used to treat breast cancer in humans (40 mg/m 2 ) according to pharmacokinetic studies (Lobo and Balthasar 2003;Ohdo et al 1997;Peters et al 1993). When 75 mg/kg 5-fluorouracil was administered prior to the day 1 session, it failed to alter response rates or acquisition latency on day 1.…”

Differences in micronucleus induction in peripheral blood reticulocytes of mice exposed to <i>N</i>-ethyl-<i>N</i>-nitrosourea at light and dark dosing times

“…In mouse bone marrow cells, approximately 70-80% of the cells are in the G1 phase with 10-20% each in the S and G2/M phases. Circadian variations have been found for each cell cycle phase with G1 cells increasing in the dark period, and S and G2/M cells increasing in the light period (Granda et al, 2005;Ohdo et al, 1997). Therefore, the cell cycle may influence the different micronuclei appearances by chemicals between light and dark dosing times.…”

Chronopharmacology and Mechanism of Antitumor Effect of Erlotinib in Lewis Tumor-Bearing Mice

“…Studies have shown that chronochemotherapy can significantly prolong the overall survival of cancer patients when compared with conventional chemotherapy and its toxicity can be controlled[23]. Recently, the best times of administration of about 30 drugs have been found, including 5-fluorouracil, methotrexate, vinorelbine, etc [24], . However, the study on chronopharmacology of molecular targeted drugs has not been reported.…”