Herb-drug interaction of Xingnaojing injection and Edaravone via pharmacokinetics, mixed inhibition of UGTs, and molecular docking

Background: Xingnaojing injection (XNJ) is a famous emergency Traditional Chinese medicine (TCM) derived from the classical Chinese prescription named An-Gong-Niu-Huang Pill. XNJ is often used along with Edaravone injection (EDA) to treat acute ischemic stroke, they have a synergistic effect in improving patients' blood coagulation and neurological function. However, this combination also causes herb-drug interactions (HDIs), raising the risk of adverse reactions. At present, little is known about the pharmacokinetics and potential mechanism of XNJ combined with EDA. Purpose: This study investigates the pharmacokinetics and potential mechanism of the HDIs between XNJ and EDA. Study design and methods: The pharmacokinetic interactions between XNJ and EDA were studied by GC-MS in rats, and the inhibition of XNJ and (-)-borneol on UDP-glucuronosyltransferase (UGTs) were assayed by LC-MS/ MS in vitro. In vitro-in vivo extrapolation (IVIVE) and molecular docking were performed to reveal the potential for HDIs. Results: The AUC0-infinity of (-)-borneol was increased by 1.25-fold in group EDA+XNJ 10 min later, and the Cmax of edaravone was increased by 1.6-fold in group XNJ+EDA 10 min later (p < 0.05). XNJ and (-)-borneol inhibited UGTs-mediated edaravone metabolism in HLM and RLM with a similar inhibitory intensity, in which both of them have stronger inhibition in RLM. These findings demonstrated that (-)-borneol in XNJ mainly exerted UGTs inhibition, which was consistent with the pharmacokinetic assays. (-)-Borneol moderately inhibited UGT2B7 and UGT1A6 by a mixed inhibition mechanism, with Ki values of 101.393 and 136.217 mu M, respectively. Due to the blood concentration of injection was dramatically increased, the HDIs caused by the inhibitory effect of XNJ on UGTs should be highly emphasized. The binding energies of (-)-borneol and edaravone toward UGT2B7 were -6.254 and -6.643 kcal/mol, and the scores towards UGT1A6 were -5.220 and -6.469 kcal/mol, respectively. Moreover, (-)-borneol has similar free energies to many drugs metabolized by UGT2B7 and UGT1A6.

Automated summary

This study investigated the pharmacokinetics and potential mechanism of herb-drug interactions (HDIs) between XNJ and EDA. The findings showed that (-)-borneol in XNJ mainly exerted UGTs inhibition, with moderate inhibition on UGT2B7 and UGT1A6. The inhibitory effect of XNJ on UGTs and the increased blood concentration of injection should be highly emphasized.