Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats

Background & Aims: Dihydroxy bile acids induce a bicarbonate-rich hyperchol eresis when secreted into canalicular bile in unconjugated form; the mechan ism is cholehepatic shunting. The aim of this study was to identify a xenob iotic that induces hypercholeresis by a similar mechanism. Methods: Five or ganic 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 chara cterized using Tr- rats (deficient in mrp2, a canalicular transporter for o rganic anions), the isolated perfused rat liver, and hepatocyte membrane fr actions. Results: In biliary fistula rats, sulindac Was recovered in bile i n unconjugated form and induced hypercholeresis of canalicular origin. Othe r 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 secre ted normally in Tr- rats, indicating that its canalicular transport did not require mrp2. In the perfused liver, sulindac inhibited cholyltaurine upta ke, and when coinfused with cholyltaurine, induced acute cholestasis. With both basolateral and canalicular membrane fractions, sulindac inhibited cho lyltaurine transport competitively. Conclusions: Sulindac is secreted into bile in unconjugated form by a canalicular bile acid transporter and is abs orbed by cholangiocytes, inducing hypercholeresis. At high flux rates, suli ndac competitively inhibits canalicular bile salt transport; such inhibitio n may contribute to the propensity of sulindac to induce cholestasis in pat ients.