Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
Phytomedicine. 2023 Apr;112:154696. doi: 10.1016/j.phymed.2023.154696. Epub 2023 Feb 4.
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.
This study investigates the pharmacokinetics and potential mechanism of the HDIs between XNJ and EDA.
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.
The AUC of (-)-borneol was increased by 1.25-fold in group EDA+XNJ 10 min later, and the C 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 K values of 101.393 and 136.217 μM, 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.
(-)-Borneol modulates the pharmacokinetic behavior of edaravone via mixed inhibition of UGT2B7 and UGT1A6. It provides a theoretical basis for the synergistic effect of XNJ and EDA combinations in clinical practice. When XNJ is used along with UGT2B7 and UGT1A6 substrates, it should be used clinically with caution.
醒脑静注射液（XNJ）是一种著名的急救中药，源自经典中药方剂安宫牛黄丸。XNJ 常与依达拉奉注射液（EDA）联合用于治疗急性缺血性脑卒中，两者在改善患者凝血功能和神经功能方面具有协同作用。然而，这种联合用药也会导致药物相互作用（HDIs），增加不良反应的风险。目前，对于 XNJ 与 EDA 联合用药的药代动力学和潜在机制知之甚少。
本研究旨在探讨 XNJ 与 EDA 之间的 HDIs 药代动力学和潜在机制。
采用 GC-MS 法在大鼠体内研究 XNJ 与 EDA 的药代动力学相互作用，采用 LC-MS/MS 法测定 XNJ 和（-）-龙脑对 UDP-葡糖醛酸基转移酶（UGTs）的抑制作用。通过体外-体内外推法（IVIVE）和分子对接揭示潜在的 HDIs 机制。
EDAXNJ10 分钟后，（-）-龙脑的 AUC 增加了 1.25 倍，XNJ+EDAXNJ10 分钟后，依达拉奉的 C 增加了 1.6 倍（p<0.05）。XNJ 和（-）-龙脑在 HLM 和 RLM 中以相似的抑制强度抑制 UGTs 介导的依达拉奉代谢，其中 RLM 中的抑制作用更强。这些发现表明，XNJ 中的（-）-龙脑主要通过 UGTs 抑制发挥作用，这与药代动力学研究结果一致。（-）-龙脑通过混合抑制机制中度抑制 UGT2B7 和 UGT1A6，K 值分别为 101.393 和 136.217μM。由于注射的血药浓度显著增加，因此应高度重视 XNJ 对 UGTs 的抑制作用引起的 HDIs。（-）-龙脑与 UGT2B7 结合的结合能为-6.254 和-6.643kcal/mol，与 UGT1A6 的结合能为-5.220 和-6.469kcal/mol。此外，（-）-龙脑与许多由 UGT2B7 和 UGT1A6 代谢的药物具有相似的自由能。
（-）-龙脑通过混合抑制 UGT2B7 和 UGT1A6 调节依达拉奉的药代动力学行为。这为 XNJ 和 EDA 联合应用于临床实践中的协同作用提供了理论依据。当 XNJ 与 UGT2B7 和 UGT1A6 底物联合使用时，应谨慎临床应用。
