title: Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats.
abstract: OBJECTIVE
  Dihydroxy bile acids induce a bicarbonate-rich hypercholeresis when secreted into canalicular bile in unconjugated form; the mechanism is cholehepatic shunting. The aim of this study was to identify a xenobiotic that induces hypercholeresis by a similar mechanism.
  
  
  METHODS
  Five organic acids (sulindac, ibuprofen, ketoprofen, diclofenac, and norfloxacin) were infused into rats with biliary fistulas. Biliary recovery, bile flow, and biliary bicarbonate were analyzed. Sulindac transport was further characterized using Tr(-) rats (deficient in mrp2, a canalicular transporter for organic anions), the isolated perfused rat liver, and hepatocyte membrane fractions.
  
  
  RESULTS
  In biliary fistula rats, sulindac was recovered in bile in unconjugated form and induced hypercholeresis of canalicular origin. Other compounds underwent glucuronidation and were not hypercholeretic. In the isolated liver, sulindac had delayed biliary recovery and induced prolonged choleresis, consistent with a cholehepatic circulation. Sulindac was secreted normally in Tr(-) rats, indicating that its canalicular transport did not require mrp2. In the perfused liver, sulindac inhibited cholyltaurine uptake, and when coinfused with cholyltaurine, induced acute cholestasis. With both basolateral and canalicular membrane fractions, sulindac inhibited cholyltaurine transport competitively.
  
  
  CONCLUSIONS
  Sulindac is secreted into bile in unconjugated form by a canalicular bile acid transporter and is absorbed by cholangiocytes, inducing hypercholeresis. At high flux rates, sulindac competitively inhibits canalicular bile salt transport; such inhibition may contribute to the propensity of sulindac to induce cholestasis in patients.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of California, San Diego, California, USA.
authors.forename: U
authors.initials: U
authors.lastname: Bolder
authors.forename: N V
authors.initials: NV
authors.lastname: Trang
authors.forename: L R
authors.initials: LR
authors.lastname: Hagey
authors.forename: C D
authors.initials: CD
authors.lastname: Schteingart
authors.forename: H T
authors.initials: HT
authors.lastname: Ton-Nu
authors.forename: C
authors.initials: C
authors.lastname: Cerrè
authors.forename: R P
authors.initials: RP
authors.lastname: Elferink
authors.forename: A F
authors.initials: AF
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism; D001646:Bile / Q000378:metabolism* / Q000502:physiology; D001648:Bile Canaliculi / Q000378:metabolism*; D001652:Bile Ducts / Q000098:blood supply*; D001658:Biliary Fistula / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001711:Biotransformation; D066298:In Vitro Techniques; D007700:Kinetics; D008102:Liver Circulation; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013467:Sulindac / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D013656:Taurocholic Acid / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001639:Bicarbonates; D013467:Sulindac; D013656:Taurocholic Acid