Skip to main content


Log in

Modified irinotecan hydrochloride (CPT-11) administration schedule improves induction of delayed-onset diarrhea in rats

  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript


Purpose: 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. Conclusion: 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Author information

Authors and Affiliations


Additional information

Received: 16 June 1999 / Accepted: 26 April 2000

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kurita, A., Kado, S., Kaneda, N. et al. Modified irinotecan hydrochloride (CPT-11) administration schedule improves induction of delayed-onset diarrhea in rats. Cancer Chemother Pharmacol 46, 211–220 (2000).

Download citation

  • Issue Date:

  • DOI: