Modified irinotecan hydrochloride (CPT-11) administration schedule improves induction of delayed-onset diarrhea in rats.
OBJECTIVE
Clinically, diarrhea is the major dose-limiting toxicity of irinotecan hydrochloride (CPT-11). Using a rat model, we attempted to decrease the incidence of delayed-onset diarrhea by modifying the administration schedule of CPT-11, and studied the pharmacokinetics in this model in relation to the incidence of diarrhea.


METHODS
CPT-11 (total dose, 240 mg/kg) was administered intravenously (i.v.) to rats according to various schedules, and the incidence of delayed-onset diarrhea was monitored.


RESULTS
Administration of CPT-11 at a dose of 60 mg/kg once daily for four consecutive days induced severe diarrhea, while at 30 mg/kg twice daily at an interval of 9 h (daily dose 60 mg/kg) for four consecutive days alleviated the diarrheal symptoms, and at 30 or 40 mg/kg once daily for eight or six consecutive days, respectively. diarrhea was hardly induced. With the first schedule, mucosal impairment of the cecal epithelium was observed, including wall thickening, edema, decrease in crypt number and size, and formation of pseudomembrane-like substance, whereas these changes were less severe with the second schedule and were hardly observed with the other two schedules. The areas under the plasma and cecal tissue concentration-time curves (AUCpla and AUCcec), the maximum plasma concentrations (Cmax) and the biliary excretions of CPT-11 and its metabolites, 7-ethyl-10-hydroxycamptothecin (SN-38) and SN-38 glucuronide (SN-38G) in rats depended on the daily dose of CPT-11. Exceptionally, CPT-11 Cmax was significantly lower and SN-38 AUCcec was larger in the animals treated at 30 mg/kg twice daily than in those treated at 60 mg/kg once daily.


CONCLUSIONS
These results suggested that the duration of exposure to both CPT-11 and SN-38 of the intestinal epithelium and CPT-11 plasma Cmax are closely related to the incidence and severity of CPT-11-induced delayed-onset diarrhea in rats.
Kurita
A
A
Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo, Japan.
Kado
S
S
Kaneda
N
N
Onoue
M
M
Hashimoto
S
S
Yokokura
T
T
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D001659:Biliary Tract / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D002432:Cecum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control*; D004334:Drug Administration Schedule; D005965:Glucuronates / Q000493:pharmacokinetics; D007082:Ileum / Q000187:drug effects / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D000077146:Irinotecan; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; D000077146:Irinotecan; D002166:Camptothecin