title: Modulated pharmacokinetics and increased small intestinal toxicity of methotrexate in bilirubin-treated rats.
abstract: OBJECTIVE
  The effect of bilirubin treatment on the pharmacokinetics and small intestinal toxicity of methotrexate was evaluated in rats, since bilirubin and its glucuronide conjugates can suppress multidrug resistance-associated protein-mediated transport.
  
  
  METHODS
  Rats were treated intravenously with bilirubin and the various clearances and tissue distribution of methotrexate were estimated under a steady-state plasma concentration. Intestinal toxicity induced by methotrexate was also evaluated by measuring the leakage of alkaline phosphatase (ALP) activity. Probenecid, an inhibitor for multidrug resistance-associated protein and organic anion transporters, was used for comparison.
  
  
  RESULTS
  The treatment with bilirubin increased the steady-state plasma concentration and reduced biliary excretion clearance, urinary excretion clearance and intestinal exsorption clearance of methotrexate, as did treatment with probenecid. The intestinal absorption and jejunum distribution of methotrexate also significantly increased in bilirubin- and probenecid-treated rats. A greater leakage of ALP activity to the luminal fluid, with a lower ALP activity in the intestinal mucosal membrane after intestinal perfusion of methotrexate, was observed in bilirubin- and probenecid-treated rats.
  
  
  CONCLUSIONS
  Hyperbilirubinemia, which is involved under various disease states, may increase the small intestinal accumulation and toxicities of methotrexate, since high plasma concentrations of conjugated bilirubin can suppress the function of multidrug resistance-associated proteins, which facilitate the efflux of methotrexate out of cells.
authors.affiliation: Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yokooji
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; D001663:Bilirubin / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D004347:Drug Interactions; D006932:Hyperbilirubinemia / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000633:toxicity*; 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; D001663:Bilirubin; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011339:Probenecid