Chronotoxicity of methotrexate in mice after intraperitoneal administration

Methotrexate (MTX), an effective agent in treatment of cancer, is one of the most versatile antineoplastic agents in spite of severe toxicity problems. The purpose of this study was to determine the circadian variation of this toxicity in order to decrease the side effects. The experiments were done in mice given a single i.p. dose. The toxicity of MTX, estimated from the relative weight loss, varied according to the time of administration, with a maximum after administration at 0900 (02 HALO). The dose-effect relationship can be described by a linear function: delta P/P versus log (dose). The slope of this line varies with the time of administration. These variations are correlated with the variations in biochemical [dihydrofolate reductase (DHFR) activity] and pharmacokinetic parameters (AUC) studied in previous works.