Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 283; no. 3; p. 1383
• Main Authors: Ohdo, S, Makinosumi, T, Ishizaki, T, Yukawa, E, Higuchi, S, Nakano, S, Ogawa, N
• Format: Journal Article
• Language: English
• Published: United States 01-12-1997
• Subjects: Animals; Antineoplastic Agents, Phytogenic - toxicity; Bone Marrow Cells - drug effects; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Camptothecin - toxicity; Cell Cycle; Circadian Rhythm; Leukocyte Count - drug effects; Male; Mice; Mice, Inbred ICR; Time Factors; Weight Loss - drug effects
• ISSN: 0022-3565

The mechanisms underlying the circadian rhythm of the toxicity induced by irinotecan hydrochloride (CPT-11; 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) were investigated from the viewpoint of the sensitivity of living organisms and the pharmacokinetics of the drug. ICR male mice were housed under standardized light-dark cycle conditions (lights on at 0700, off at 1900) with food and water ad libitum. The loss of body weight after an intraperitoneal injection of CPT-11 (100 mg/kg) was more serious in the late dark and the early light and milder in the late light and the early dark. The CPT-11-induced leukopenia was more serious in the late dark and milder in the late light. The lower toxicity of CPT-11 was observed when DNA synthesis and type I DNA topoisomerase activity in bone marrow cells decreased and the higher toxicity was observed when these activities began to increase. There were circadian stage-dependent changes in the concentrations of CPT-11 and its major metabolite (SN-38; 7-ethyl-10-hydroxycamptothecin) in plasma. The higher concentrations of CPT-11 and SN-38 in plasma were observed when the level of CPT-11-induced toxicity increased. The present study suggests that the toxicity of CPT-11 is influenced by circadian rhythm-dependent processes.