DataSheet1_Integrated serum pharmacochemistry, pharmacokinetics, and network analysis to explore active components of BuShao Tiaozhi Capsule on hyperlipidemia.docx

BuShao Tiaozhi Capsule (BSTZC), a novel drug in China, has been used to treat hyperlipidemia (HLP) in clinical practice for many years. Despite our previous studies suggesting that BSTZC can treat HLP, there is a lack of a rapid and systematic method to explore its active components. Therefore, in this study, we aimed to investigate the active components and mechanisms of BSTZC in treating HLP by integrating serum pharmacology, pharmacokinetics, network analysis, and experimental validation. We first established UPLC fingerprints, calibrated 23 common peaks, and identified 13 common peaks, and the similarity was greater than 0.99 for 10 batches. A total of nine metabolites from BSTZC were identified in serum and considered as PK markers. The pharmacokinetic parameters of the PK markers were compared between the control group and the model group through the pharmacokinetics study to determine the dynamic changes of representative components in rats. Compared with the control group, the Cmax and AUC0→t of OXY, IVT, IVL, and KPF-3-G were significantly higher (P< 0.05); the AUC0→∞ of OXY, PN, and IVT was significantly higher (P< 0.05); and the t1/2 of IVT, SA, and KPF-3-G was significantly different (P< 0.05). In vivo experiments showed that BSTZC and its active components could effectively alleviate lipid metabolism disorders and liver injury, with obvious lipid-lowering effects. Further studies showed that BSTZC alleviated HLP by inhibiting the PI3K/Akt signaling pathway, which was consistent with the results of the network analysis study. Our results revealed the active components and mechanisms of BSTZC in the treatment of HLP, which could provide useful information to guide the clinical application of BSTZC.

补肾调脂胶囊（BuShao Tiaozhi Capsule, BSTZC）是我国一款新型药物，已在临床用于高脂血症（hyperlipidemia, HLP）的治疗多年。尽管既往研究证实补肾调脂胶囊可用于高脂血症的治疗，但目前尚缺乏快速系统的方法探究其活性成分。为此，本研究整合血清药理学、药物代谢动力学、网络分析与实验验证技术，旨在探究补肾调脂胶囊治疗高脂血症的活性成分及其作用机制。本研究首先建立了超高效液相色谱（UPLC）指纹图谱，标定23个共有峰并指认其中13个共有峰，10批样品的指纹图谱相似度均大于0.99。从大鼠血清中鉴定出补肾调脂胶囊来源的9种代谢物，将其作为药代动力学（PK）标志物。通过药代动力学实验，对比对照组与模型组中药代动力学标志物的参数，以明确大鼠体内代表性成分的动态变化规律。与对照组相比，OXY、IVT、IVL及KPF-3-G的峰浓度（Cmax）和0~t时间曲线下面积（AUC0→t）均显著升高（P<0.05）；OXY、PN及IVT的0~∞时间曲线下面积（AUC0→∞）显著升高（P<0.05）；IVT、SA及KPF-3-G的半衰期（t1/2）存在显著差异（P<0.05）。体内实验结果表明，补肾调脂胶囊及其活性成分可有效改善脂质代谢紊乱与肝损伤，具备显著的调脂疗效。进一步研究证实，补肾调脂胶囊通过抑制PI3K/Akt信号通路发挥改善高脂血症的作用，该结果与网络分析的结论一致。本研究明确了补肾调脂胶囊治疗高脂血症的活性成分及其作用机制，可为其临床合理应用提供科学依据。