Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice.
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.
Ohdo
S
S
Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812 Japan.
Makinosumi
T
T
Ishizaki
T
T
Yukawa
E
E
Higuchi
S
S
Nakano
S
S
Ogawa
N
N
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D002453:Cell Cycle; D002940:Circadian Rhythm; D000077146:Irinotecan; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013997:Time Factors; D015431:Weight Loss / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin