title: Impact of Mrp2 on the biliary excretion and intestinal absorption of furosemide, probenecid, and methotrexate using Eisai hyperbilirubinemic rats.
abstract: OBJECTIVE
  This study assesses the impact of rat multidrug resistance-associated protein 2 (Mrp2) on the biliary excretion and oral absorption of furosemide, probenecid, and methotrexate using Eisai hyperbilirubinemic rats (EHBR).
  
  
  METHODS
  To assess Mrp2-mediated biliary excretion, rats received a 2-h intravenous infusion of furosemide, probenecid, or methotrexate. Blood and bile samples were collected at specified intervals. To assess Mrp2's impact on oral absorption, rats received furosemide, probenecid, or methotrexate orally at 5 mg/kg. Jugular and portal blood samples were obtained at timed intervals. All samples were analyzed by LC-MS/MS. Pharmacokinetic parameters were estimated using WinNonlin and standard pharmacokinetic equations.
  
  
  RESULTS
  Thirty seven- and 39-fold reductions in biliary clearance were observed in EHBR as compared to control rats for probenecid and methotrexate, respectively. Biliary clearance was comparable between EHBR and control rats for furosemide. In all cases, no significant difference in absorption was observed between EHBR and control rats.
  
  
  CONCLUSIONS
  This study provides the first evidence that Mrp2 mediates the biliary excretion of probenecid but not furosemide. Additionally, Mrp2 apparently has a less profound impact on intestinal absorption than biliary excretion of its substrates. Furthermore, alteration in systemic clearance in EHBR indicates that a potential compensatory mechanism may occur in EHBR.
authors.affiliation: Groton Laboratory, Pfizer Global Research and Development, Pfizer Inc, Eastern Point Road, Groton, Connecticut 06340, USA. cuiping_chen@groton.pfizer.com
authors.forename: Cuiping
authors.initials: C
authors.lastname: Chen
authors.forename: Dennis
authors.initials: D
authors.lastname: Scott
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hanson
authors.forename: Judy
authors.initials: J
authors.lastname: Franco
authors.forename: Edwin
authors.initials: E
authors.lastname: Berryman
authors.forename: Mario
authors.initials: M
authors.lastname: Volberg
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005665:Furosemide / Q000097:blood / Q000493:pharmacokinetics*; D006932:Hyperbilirubinemia / Q000235:genetics / Q000378:metabolism*; D007408:Intestinal Absorption / Q000502:physiology; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics*; D011339:Probenecid / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D002352:Carrier Proteins; D005665:Furosemide; D011339:Probenecid; D008727:Methotrexate