Study on the mechanisms of diarrhea induced by a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats.

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  • TAKASUNA Kiyoshi
    Drug Safety Research Center, Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd.
  • KASAI Yoshio
    Drug Safety Research Center, Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd.
  • KITANO Yutaka
    Drug Safety Research Center, Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd.
  • MORI Kazuhiko
    Drug Safety Research Center, Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd.
  • KAKIHATA Kohji
    Drug Safety Research Center, Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd.
  • HIROHASHI Masaaki
    Drug Safety Research Center, Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd.
  • NOMURA Mamoru
    Drug Safety Research Center, Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd.

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Other Title
  • 新規抗腫よう薬塩酸イリノテカン（ＣＰＴ‐１１）の下痢誘発機序に関する研究
  • シンキ コウ シュヨウヤク エンサン イリノテカン CPT-11 ノ ゲリ ユ

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Abstract

We investigated the mechanisms of CPT-11-induced diarrhea. 1) CPT-11 (80 mg/kg, i.v.) induced watery diarrhea within 1 hr after dosing in saline-loaded (10 ml/kg, p.o.) rats. This was partially inhibited by subcutaneous injection of atropine (1 mg/kg) or ondansetron (1 mg/kg) and almost completely inhibited by a combination of atropine and ondansetron or by clonidine (0.3 mg/kg) or morphine (10 mg/kg) alone. 2) CPT-11 at the same dose reduced intestinal fluid absorption, which was blocked by the anti-diarrheal agents mentioned above. Intraluminal injection of CPT-11 (20 mg/2 ml) inhibited fluid absorption and induced fluid secretion. 3) CPT-11, 60 mg/kg, by single intravenous injection induced fewer enzymological and histological changes in the small intestine than 5-FU at 270 mg/kg, while 4 consecutive dosings of CPT-11 induced delayed diarrhea (days 5-7) associated with disruption of intestinal integrity. Co-administration with antidiarrheal agents, except for ondansetron, protected against watery diarrhea appearing within 1 hr after CPT-11 on days 3 and 4, but worsened delayed diarrhea. These results suggest that single injection of higher doses of CPT-11 causes watery diarrhea at an acute phase at least partly by reducing fluid absorption or increasing secretion, and that while conventional anti-diarrheal agents protect against watery diarrhea, their co-administration in repeated CPT-11 administration has no ameliorative effect on CPT-11 -induced delayed diarrhea.

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