Yoshio Kase (1), Terumasa Hayakawa (1), Yuji Togashi (1) and Tetsuya
Kamataki (2)
(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