Antibiotic pretreatment promotes orally-administered triptolide absorption and aggravates hepatotoxicity and intestinal injury in mice

Triptolide (TP) exhibits extensive pharmacological activity, but its hepatotoxicity and intestinal injury are significant and limit its clinical use.To investigate the effect of gut microbiota disturbance after antibiotic pretreatment on TP-induced hepatotoxicity, intestinal injury and their mechanism.We compared the characteristics of TP-induced hepatotoxicity and intestinal injury in mice with or without antibiotic pretreatment. The levels of cytokines in the serum, immunohistochemistry, and the pharmacokinetics of TP were determined.Antibiotic pretreatment aggravates TP-induced hepatotoxicity and ileum/colon injury. TP induces hepatotoxicity in a dose-dependent manner after antibiotic pretreatment. Serum IL-1β and IL-6 levels were increased in mice given oral TP after antibiotic pretreatment. TP can increase the expression of NLRP3 inflammasome in hepatocytes, and Oral TP after antibiotic pretreatment can significantly enhance its expression, but NLRP3 inflammasome no significant change in colon and ileum. The pharmacokinetic characteristics of TP are altered significantly by antibiotic pretreatment, as shown by a 145.87% increase in Cmax, a 155.11% increase in AUC0-t, a 155.1% increase in relative bioavailability, and a 15.44% delay in MRT. Moreover, TP causes hepatotoxicity in a time-dependent manner.Antibiotic pretreatment aggravates triptolide-induced hepatotoxicity and intestinal injury through elevated inflammatory response and promoted triptolide absorption.