Non-steroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal injury is a serious clinical event with recent advances of diagnostic technologies, but a successful therapeutic method to treat such injuries is still lacking. Licorice, a traditional herbal medicine, and its derivatives have been widely used for the treatment of a variety of diseases due to their extensive biological actions. However, it is unknown whether these derivatives have an effect on NSAIDs-induced small intestinal damage. Previously, the anti-inflammatory effects of three compounds extracted from the licorice root, glycyrrhizin, 18 beta-glycyrrhetinic acid, and dipotassium glycyrrhizinate, were compared in vitro cell culture. The most prominent inhibitory effect on the tumor necrosis factor-alpha (TNF-alpha) production was observed with the administration of 18 beta-glycyrrhetinic acid as an active metabolite of glycyrrhizin. In this study, a complex compound of 18 beta-glycyrrhetinic acid and hydroxypropyl gamma cyclodextrin was examined to improve the oral bioavailability. After administration of this complex to indomethacin treated mice, a significantly high plasma concentration of 18 beta-glycyrrhetinic acid was detected using the tandem mass spectrometry coupled with the HPLC. Furthermore, the complex form of 18 beta-glycyrrhetinic acid and hydroxypropyl gamma cyclodextrin reduced mRNA expressions of TNF-alpha, interleukin (IL)-1 beta, and IL-6, which was histologically confirmed in the improvement of indomethacin-induced small intestinal damage. These results suggest that the complex of 18 beta-glycyrrhetinic acid and hydroxypropyl gamma cyclodextrin has the potential therapeutic value for preventing the adverse effects of indomethacin-induced small intestinal injury. (c) 2013 Elsevier B.V. All rights reserved.