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Vol. 283, Issue 3, 1383-1388, 1997

Cell Cycle-Dependent Chronotoxicity of Irinotecan Hydrochloride in Mice

Shigehiro Ohdo, Tomoko Makinosumi, Takashi Ishizaki, Eiji Yukawa, Shun Higuchi, Shigeyuki Nakano and Nobuya Ogawa

Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812 Japan (S.O., T.M., T.I., E.Y., S.H.); Department of Clinical Pharmacology and Therapeutics, Oita Medical University, Hasama-Machi, Oita 879-55, Japan (S.N.) and Department of Pharmacology, Ehime University School of Medicine, Shigenobu-Cho, Onsen-Gun, Ehime 791-02 (N.O.)

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.

0022-3565/97/2833-1383$03.00/0
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1997 by the American Society for Pharmacology and Experimental Therapeutics.