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Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride (CPT-11)-induced delayed diarrhea

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Abstract

Purpose: An antitumor camptothecin derivative CPT-11 has proven a broad spectrum of solid tumor malignancy, but its severe diarrhea has often limited its more widespread use. We have demonstrated from a rat model that intestinal β-glucuronidase may play a key role in the development of CPT-11-induced delayed diarrhea by the deconjugation of the luminal SN-38 glucuronide, and the elimination of the intestinal microflora by antibiotics or dosing of TJ-14, a Kampo medicine that contains β-glucuronidase inhibitor baicalin, exerted a protective effect. In the present study, we assessed the efficacy of several potential treatments in our rat model to clarify which is the most promising treatment for CPT-11-induced delayed diarrhea. Methods and results: Oral dosing (twice daily from days −1 to 4) of streptomycin 20 mg/kg and penicillin 10 mg/kg (Str/Pen), neomycin 20 mg/kg and bacitracin 10 mg/kg (Neo/Bac), both of which inhibited almost completely the fecal β-glucuronidase activity, or TJ-14 1,000 mg/kg improved the decrease in body weight and the delayed diarrhea symptoms induced by CPT-11 (60 mg/kg i.v. from days 1 to 4) to a similar extent. The efficacy was less but significant in activated charcoal (1,000 mg/kg p.o. twice daily from days −1 to 4). In a separate experiment using rats bearing breast cancer (Walker 256-TC), TJ-14, Neo/Bac, and charcoal at the same dose regimen improved CPT-11-induced intestinal toxicity without reducing CPT-11’s antitumor activity. In contrast, oral dosing (twice a day) of cyclosporin A (50 mg/kg), a P-glycoprotein and cMOAT/MRP2 inhibitor or valproic acid (200 mg/kg), a UDP-glucuronosyltranferase inhibitor, exacerbated the intestinal toxicity without modifying CPT-11’s antitumor activity. Conclusions: The result clearly demonstrated the ability of Neo/Bac, Str/Pen, and TJ-14, less but significant ability of activated charcoal, to ameliorate CPT-11-induced delayed-onset diarrhea, suggesting the treatments decreasing the exposure of the intestines to the luminal SN-38 are valuable for improvement of CPT-11-induced intestinal toxicity. In contrast, the treatments affecting the biliary excretion of CPT-11 and its metabolites might have undesirable results.

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Authors and Affiliations

  1. New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., 16-13 Kita-kasai 1-chome, Edogawa-ku, 134-8630, Tokyo, Japan

    K. Takasuna, T. Hagiwara, K. Watanabe & S. Onose

  2. New Product Research Laboratories III, Daiichi Pharmaceutical Co., Ltd., 16-13 Kita-kasai 1-chome, Edogawa-ku, 134-8630, Tokyo, Japan

    S. Yoshida & E. Kumazawa

  3. International Marketing Department, Medical Communications Group, Daiichi Pharmaceutical Co., Ltd., 16-13 Kita-kasai 1-chome, Edogawa-ku, 134-8630, Tokyo, Japan

    E. Nagai

  4. Division of Drug Metabolisms, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, 060, Sapporo, Japan

    T. Kamataki

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  1. K. Takasuna
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Takasuna, K., Hagiwara, T., Watanabe, K. et al. Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride (CPT-11)-induced delayed diarrhea. Cancer Chemother Pharmacol 58, 494–503 (2006). https://doi.org/10.1007/s00280-006-0187-8

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