Indomethacin is a powerful analgesic NSAID, but is limited in use by its side effect to cause gastrointestinal bleeding. One factor important for exacerbating NSAID injury is the presence of bile acids which may interact with indomethacin to form toxic mixed micelles in the gut. The development of a GI-safer formulation of indomethacin that is chemically complexed with phosphatidylcholine (PC-indomethacin) may offer an improved therapeutic agent, particularly in the presence of bile acid, but its protective mechanism is incompletely understood. Intestinal epithelial cells (IEC-6) were tested for injury with indomethacin compared to PC-indomethacin (alone and plus bile acids). To explore a role for cellular bile acid uptake as a requirement for NSAID injury, studies were performed using MDCK cells transfected with the apical sodium-dependent bile acid transporter (ASBT). Indomethacin, but not PC-indomethacin, was directly and dose-dependently injurious to IEC-6 cells. Similarly, the combination of any bile acid plus indomethacin, but not PC-indomethacin, induced cell injury. The expression of ASBT did not appear to affect the acute cytotoxicity of indomethacin in the presence of bile acids. Complexing PC with indomethacin protected against the acute intestinal epithelial injury caused by indomethacin regardless of the presence of bile acids. The presence of luminal bile acid, but not its carrier-mediated uptake into the enterocyte is required for acute indomethacin-induced cell injury. It is likely that initial cell damage induced by indomethacin occurs at or near the cell membrane, an effect exacerbated by bile acids and attenuated by PC.
- Copyright © 2014, American Journal of Physiology- Gastrointestinal and Liver Physiology