Effect of genistein, a natural soy isoflavone, on the pharmacokinetics and intestinal toxicity of irinotecan hydrochloride in rats

Authors

  • Tomoharu Yokooji,

    1. Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan
    Current affiliation:
    1. Department of Pathophysiology and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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  • Yoshihiro Kawabe,

    1. Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan
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  • Nobuhiro Mori,

    1. Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan
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  • Teruo Murakami

    Corresponding author
    • Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan
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Correspondence

Teruo Murakami, Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure 737-0112, Japan.

E-mail: t-muraka@ps.hirokoku-u.ac.jp

Abstract

Objectives

The effect of genistein, a natural soy isoflavone, on pharmacokinetics and intestinal toxicity, or late-onset diarrhoea, of irinotecan hydrochloride (CPT-11) was examined in rats.

Methods

Probenecid, a typical inhibitor of multidrug resistance-associated protein (MRP) 2, was also employed for comparison with genistein. Plasma concentration, biliary excretion and intestinal secretion of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38) and SN-38 glucuronide (SN-38G) were determined in untreated, genistein-treated and probenecid-treated rats. CPT-11 was administered repeatedly by intravenous injection (60 mg/kg/day for 4 days), and the effects of genistein and probenecid on CPT-11-induced intestinal toxicity were evaluated by measuring body weight, induction of diarrhoea, and alkaline phosphatase (ALP) activity in the intestinal mucosal membranes.

Key findings

Genistein, as well as probenecid, significantly suppressed the MRP2-mediated biliary and intestinal secretion of CPT-11 and its metabolites and increased their plasma concentrations. Multiple administration of CPT-11 reduced body weight and ALP activity, and induced watery diarrhoea. Genistein, as well as probenecid, significantly suppressed the loss in body weight and the reduced mucosal ALP activity in the ileum, and ameliorated the symptoms of diarrhoea induced by CPT-11.

Conclusions

Intravenous genistein was effective in ameliorating CPT-11-induced late-onset diarrhoea, by suppressing MRP2-mediated biliary excretion of CPT-11 and its metabolites.

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