Xuezhikang capsule (XZK) is a traditional Chinese medicine that contains lovastatin (Lv) for hyperlipidemia treatment, although it has fewer side effects than Lv. However, the pharmacokinetic mechanisms contributing to its distinct efficacy and low side effects are unclear. Mice were fed a high-fat diet (HFD) for 6 weeks to induce hyperlipidemia. We first conducted the pharmacokinetic studies in HFD mice following oral administration of Lv (10 mg/kg, i.g.) and found that HFD remarkably decreased the active form of Lv (the lovastatin acid, LvA) exposure in the circulation system, especially in the targeting organ liver, with a declined conversion from Lv to LvA, whereas the Lv (responsible for myotoxicity) exposure in muscle markedly increased. Then we compared the pharmacokinetic profiles of Lv in HFD mice after the oral administration of XZK (1200 mg/kg, i.g.) or an equivalent dose of Lv (10 mg/kg, i.g.). A higher exposure of LvA and lower exposure of Lv were observed after XZK administration, suggesting a pharmacokinetic interaction of some ingredients in XZK. Further studies revealed that HFD promoted the inflammation and inhibited carboxylesterase (CES) activities in the intestine and the liver, thus contributing to the lower transformation of Lv into LvA. In contrast, XZK inhibited the inflammation and upregulated CES in the intestine and the liver. Finally, we evaluated the effects of monacolins and phytosterols, the fractional extracts of isoflavones, on inflammatory LS174T or HepG2 cells, which showed that isoflavones inhibited inflammation, upregulated CES, and markedly enhanced the conversion of Lv into LvA. For the first time, we provide evidence that isoflavones and Lv in XZK act in concert to enhance the efficacy and reduce the side effects of Lv.

中文翻译：

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异黄酮口服血脂康胶囊后，可通过上脂饮食小鼠体内的羧酸酯酶上调来增强活性洛伐他汀酸的药代动力学暴露。

血脂康胶囊（XZK）是一种含有洛伐他汀（Lv）的中药，可治疗高脂血症，尽管其副作用比Lv少。然而，尚不清楚其独特功效和低副作用的药代动力学机制。给小鼠喂食高脂饮食（HFD）6周，以诱导高脂血症。口服Lv（10 mg / kg，ig）后，我们首先在HFD小鼠中进行了药代动力学研究，发现HFD显着降低了循环系统中Lv（洛伐他汀酸，LvA）的活性形式暴露，特别是在靶向治疗中器官肝脏，从Lv到LvA的转化率下降，而肌肉中的Lv（负责肌毒性）暴露显着增加。然后，我们比较了口服XZK（1200 mg / kg，ig）或当量Lv（10 mg / kg，ig）后在HFD小鼠中Lv的药代动力学特征。XZK给药后观察到较高的LvA暴露量和较低的Lv暴露量，表明XZK中某些成分的药代动力学相互作用。进一步的研究表明，HFD促进了肠道和肝脏的炎症反应并抑制了羧酸酯酶（CES）的活性，从而有助于Lv转化为LvA的程度降低。相比之下，XZK抑制了肠道和肝脏的炎症并上调了CES。最后，我们评估了莫纳可林和植物甾醇（异黄酮的部分提取物）对炎症性LS174T或HepG2细胞的影响，结果表明异黄酮可以抑制炎症，上调CES，并显着增强了Lv向LvA的转化。我们首次提供证据，证明XZK中的异黄酮和Lv协同发挥作用，以增强功效并减少Lv的副作用。