Importance of biliary excretion of indomethacin in gastrointestinal and hepatic injury

Abstract

A mechanism for protection of gastrointestinal (GI) and hepatic cells from damaging detergent actions of bile acids appears to involve the bile component, phosphatidylcholine (PC). Non-steroidal anti-inflammatory drugs (NSAIDs) induce intestinal injury in direct proportion to their ability to be excreted into bile, and are known to chemically associate with PC. We investigated the role of bile acids and PC in the mechanism of indomethacin-induced epithelial injury. Rats were injected orally or intravenously with radiolabeled indomethacin and their bile was collected over time for determination of NSAID secretion. Bile from rats treated with or without indomethacin was used in studies of red blood cell (RBC) hemolysis as a measure of membrane cytotoxicity. The bile salt, sodium deoxycholate (SDC), and indomethacin were tested alone and in combination with PC on RBC and on hepatic HepG2 cells. Intravenously or orally given indomethacin was quantitatively excreted (approximately 50%) into bile over a 2-h study period. Bile from a rat treated with indomethacin or bile with exogenous indomethacin was cytotoxic to RBC, and the injury was prevented by the addition of PC. Hepatocytes exposed to SDC showed injury that could be dose-dependently prevented by PC, and reversed by indomethacin. Biliary PC plays an important physiological role in protecting GI and hepatic epithelia from the cytotoxic actions of bile salts. The ability of NSAIDs excreted into the bile to associate with mixed bile salt micelles and reduce the protective action of the PC may be a critical component in the drugs' pathogenic mechanism.