Cell Cycle-Dependent Chronotoxicity of Irinotecan Hydrochloride in Mice
- Shigehiro Ohdo1,
- Tomoko Makinosumi1,
- Takashi Ishizaki1,
- Eiji Yukawa1,
- Shun Higuchi1,
- Shigeyuki Nakano2 and
- Nobuya Ogawa3
- 1Department 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.); 2Department of Clinical Pharmacology and Therapeutics, Oita Medical University, Hasama-Machi, Oita 879–55, Japan (S.N.) and 3Department of Pharmacology, Ehime University School of Medicine, Shigenobu-Cho, Onsen-Gun, Ehime 791–02 (N.O.)
Abstract
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.
Footnotes
-
Send reprint requests to: Shigehiro Ohdo, Ph.D., Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Kyushu University, 3–1-1, Maidashi, Higashi-Ku, Fukuoka, 812 Japan.
- Abbreviations:
- CPT
- camptothecin
- CPT-11
- irinotecan hydrochloride, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin
- SN-38
- 7-ethyl-10-hydroxycamptothecin
- Topo I
- type I DNA topoisomerase
- HPLC
- high pressure liquid chromatography
- AUC
- area under the plasma-time concentration curve
- MRT
- mean residence time
- VRT
- variance of residence time
- EDTA
- ethylenediaminetetraacetic acid
- I.D.
- internal diameter
-
- Received April 29, 1997.
- Accepted August 11, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
