title: Effect of genistein, a natural soy isoflavone, on the pharmacokinetics and intestinal toxicity of irinotecan hydrochloride in rats.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
authors.affiliation: Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yokooji
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawabe
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Mori
authors.forename: Teruo
authors.initials: T
authors.lastname: Murakami
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D003967:Diarrhea / Q000139:chemically induced; D004347:Drug Interactions; D019833:Genistein / Q000494:pharmacology*; D005965:Glucuronates / Q000097:blood; D020719:Glucuronides / Q000097:blood; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects*; D000077146:Irinotecan; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000469:Alkaline Phosphatase; D002166:Camptothecin; D019833:Genistein; D005965:Glucuronates; D020719:Glucuronides; D000077146:Irinotecan; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011339:Probenecid; C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; C441475:7-ethyl-10-hydroxycamptothecin glucuronide