Wu Fan, Wang Yan, Mei Quanxi, Chen Qinhua, Sun Chengpeng, Lv Xia, Feng Lei, Wang Chao, Zhang Yanyan, Fang Bangjiang, Huo Xiaokui, Tian Xiangge, Ma Xiaochi
Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, China.
Institute of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
J Ethnopharmacol. 2023 Mar 25;304:116016. doi: 10.1016/j.jep.2022.116016. Epub 2022 Dec 16.
Jinhongtang, a traditional Chinese medicine (TCM) formula consisting of dry stems of Rheum palmatum L. (Polygonaceae) and Sargentodoxa cuneata (Oliv.) Rehder & E.H.Wilson (Lardizabalaceae) and whole plant of Taraxacum mongolicum Hand.-Mazz. (Asteraceae), is widely used for the treatment of infection diseases including severe sepsis and COVID-19.
The present study aimed to explore the compatibility mechanism in the prescription of Jinhongtang based on the pharmacokinetic interaction.
CLP-induced sepsis mice and LPS-induced RAW264.7 cells were used to explore the anti-inflammatory effect of Jinhongtang and herbs in this clinical prescription. Pharmacokinetics of active components in Jinhongtang (Rhein, Emodin and Aloe emodin) was studied in rats. In vitro analysis of metabolic pathways and interactions mediated by metabolic enzymes were conducted using human liver microsomes (HLMs) and recombinant UGT isoforms.
Jinhongtang exhibited much more potent anti-inflammatory effect than its single herbs on CLP-induced sepsis mice and LPS-induced RAW264.7 cells. Next, the bioavailability of active ingredients (Rhein, Emodin and Aloe emodin) in R. palmatum was significantly improved through reduced metabolic clearance when co-administered with S. cuneata and T. mongolicum as Jinhongtang during the in vivo pharmacokinetic study, which presented the rational herbal compatibility mechanism. In detailed, the components in S. cuneata and T. mongolicum including Sargentodoxoside A, Chanitracin Ia, Quercetin and Luteolin inhibited the UGT1A9-mediated glucuronidation of active ingredients in R. palmatum, with K values of 2.72 μM, 1.25 μM, 2.84 μM and 0.83 μM, respectively.
T. mongolicum and S. cuneata, the adjuvant herbs of Jinhongtang, could reduce the metabolic clearance of key active components of R. palmatum, prolong their action time and further enhance their anti-inflammatory activity via inhibition of UGTs. Our findings provided deep insight for the rational compatibility of TCMs and useful guidance for the development of TCM formula.
金黄汤是一种中药配方，由掌叶大黄（蓼科）、大血藤（木通科）的干燥茎以及蒙古蒲公英（菊科）的全草组成，广泛用于治疗包括严重脓毒症和新冠肺炎在内的感染性疾病。
本研究旨在基于药代动力学相互作用探索金黄汤处方中的配伍机制。
采用盲肠结扎穿孔术（CLP）诱导的脓毒症小鼠和脂多糖（LPS）诱导的RAW264.7细胞，探索金黄汤及其方中各味中药的抗炎作用。在大鼠中研究了金黄汤中活性成分（大黄酸、大黄素和芦荟大黄素）的药代动力学。使用人肝微粒体（HLM）和重组UGT同工型对代谢途径以及代谢酶介导的相互作用进行体外分析。
在CLP诱导的脓毒症小鼠和LPS诱导的RAW264.7细胞中，金黄汤表现出比其单味中药更强的抗炎作用。其次，在体内药代动力学研究中，当掌叶大黄与大血藤和蒙古蒲公英作为金黄汤合用时，掌叶大黄中活性成分（大黄酸、大黄素和芦荟大黄素）的代谢清除率降低，生物利用度显著提高，这体现了合理的中药配伍机制。具体而言，大血藤和蒙古蒲公英中的成分，包括大血藤苷A、链格孢菌素Ia、槲皮素和木犀草素，抑制了掌叶大黄中活性成分的UGT1A9介导的葡萄糖醛酸化，K值分别为2.72 μM﹑1.25 μM﹑2.84 μM和0.83 μM。
金黄汤的佐药蒙古蒲公英和大血藤可降低掌叶大黄关键活性成分的代谢清除率，延长其作用时间，并通过抑制UGTs进一步增强其抗炎活性。我们的研究结果为中药的合理配伍提供了深入见解，并为中药配方的开发提供了有用指导。
