Emodin‐induced hepatotoxicity was exacerbated by probenecid through inhibiting UGTs and MRP2

ABSTRACT Aggravating effect of probenecid (a traditional anti‐gout agent) on emodin‐induced hepatotoxicity was evaluated in this study. 33.3% rats died in combination group, while no death was observed in rats treated with emodin alone or probenecid alone, indicating that emodin‐induced (150mg/kg) hepatotoxicity was exacerbated by probenecid (100mg/kg). In toxicokinetics‐toxicodynamics (TK‐TD) study, aspartate aminotransferase (AST) and systemic exposure (area under the serum concentration‐time curve, AUC) of emodin and its glucuronide were significantly increased in rats after co‐administrated with emodin and probenecid for 28 consecutive days. Results showed that the increased AUC (increased by 85.9%) of emodin was mainly caused by the decreased enzyme activity of UDP‐glucuronosyltransferases (UGTs, decreased by 11.8%–58.1%). In addition, AUC of emodin glucuronide was increased 5‐fold, which was attributed to the decrease of multidrug‐resistant‐protein 2 (MRP2) protein levels (decreased by 54.4%). Similarly, in vitro experiments proved that probenecid reduced the cell viability of emodin‐treated HepG2 cells through inhibiting UGT1A9, UGT2B7 and MRP2. Our findings demonstrated that emodin‐induced hepatoxicity was exacerbated by probenecid through inhibition of UGTs and MRP2 in vivo and in vitro, indicating that gout patients should avoid taking emodin‐containing preparations in combination with probenecid for a long time. HIGHLIGHTSCombined use of emodin‐containing preparations with probenecid to treat goutThis is the first research on the interactions between emodin and probenecid.Long‐term use of high‐dose emodin could cause hepatotoxicity.Emodin‐induced hepatotoxicity is exacerbated by probenecid.Probenecid inhibits UGTs and MRP2 and thus exacerbates emodin hepatotoxicity.