Yoshio Kase (1), Terumasa Hayakawa (1), Yuji Togashi (1) and Tetsuya
(1) Central Research Laboratories, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-11, Japan
(2) Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060, Japan
Abstract: For characterization of the mechanism(s) of severe diarrhea due to the anticancer agent, irinotecan hydrochloride (CPT-11), examination was made of the relation of CPT-11-related diarrhea to colonic prostaglandin E2 (PGE2) and water absorption in rats. Acute diarrheal symptoms were observed within 1 hr after the administration of CPT-11 to rats, with increased PGE2 and decreased water absorption in the colon. Treatment with atropine at 1 mg/kg, s.c. was noted to inhibit intestinal PGE2 and the CPT-11-related acute diarrheal symptoms, indicating that these diarrheal symptoms were mediated through the cholinergic nervous system accelerated functionally by CPT-11. On the other hand, daily treatment of CPT-11 at the same dose resulted in chronic diarrheal symptoms in all animals 3 days after CPT-11 treatment. Histopathological changes observed in the descending colon and ileum of the rats included degeneration and necrosis of villi and cryptal cells and a decrease in the number of the goblet cells. Significantly increased PGE2 and impaired water absorption of the descending colon were also observed during the chronic diarrheal stage. It can be considered that the chronic diarrheal symptoms appear as a consequence of the gastrointestinal injury characterized by significant increase in PGE2 accompanied by impaired water absorption.
Keywords: CPT-11 (irinotecan hydrochloride), Side effect, Diarrhea, Colon, Prostaglandin E2