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RESEARCH PAPER
Effect of genistein, a natural soy isoflavone, on the pharmacokinetics and intestinal toxicity of irinotecan hydrochloride in rats
Article first published online: 21 SEP 2012
DOI: 10.1111/j.2042-7158.2012.01592.x
© 2012 The Authors. JPP © 2012. Royal Pharmaceutical Society
Additional Information
How to Cite
Yokooji, T., Kawabe, Y., Mori, N. and Murakami, T. (2013), Effect of genistein, a natural soy isoflavone, on the pharmacokinetics and intestinal toxicity of irinotecan hydrochloride in rats. Journal of Pharmacy and Pharmacology, 65: 280–291. doi: 10.1111/j.2042-7158.2012.01592.x
Publication History
- Issue published online: 26 DEC 2012
- Article first published online: 21 SEP 2012
- Manuscript Accepted: 13 AUG 2012
- Manuscript Received: 2 MAR 2012
- Abstract
- Article
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- Cited By
Keywords:
- genistein;
- intestinal toxicity;
- irinotecan hydrochloride;
- late-onset diarrhoea;
- multidrug resistance-associated protein 2
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.