天然生物活性分子是新药开发的重要来源。然而，它们中的大多数由于其低水溶性和生物利用度而限制了临床应用。冬凌草甲素(ORI)是一种具有上述特性的强效抗癌化合物。本研究旨在寻找一种有效方法来提高难溶性天然化合物的生物利用度，并探讨其作用机制，以促进其应用。本研究中，ORI-烟酰胺（NCT）首次成功制备共晶，克服了ORI的缺陷。共晶(COC)的溶解度和口服生物利用度较ORI增加1.34和1.18倍。此外，采用MTT法比较阳性对照药索拉非尼与ORI和COC的细胞毒性。索拉非尼、ORI和COC对HepG2细胞的IC50值分别为7.61、8.79和7.36 nmol·mL-1，表明共晶制剂可以增强ORI的细胞毒性。创新性地引入细胞代谢组学，深入了解ORI和COC细胞毒性机制的差异。结果显示，两组之间有78种含量存在显着差异的代谢物，而这些差异代谢物与11条代谢途径相关。其中，甘油磷脂代谢和半胱氨酸和蛋氨酸代谢是显着差异途径，PC(14:0/16:1(9z))的下调和同型半胱氨酸的上调可能是COC细胞毒性较高的主要原因。提出了增强天然化合物生物利用度和药效的新方法，同时还为药物共晶体的潜在作用机制提供了新的见解。版权所有 © 2023 Elsevier GmbH。版权所有。

Natural bioactive molecules are important sources for the development of new drugs. However, most of them were limited in clinical applications due to their low aqueous solubility and bioavailability. Oridonin (ORI) is a powerful anticancer compound with above characteristics.This study aimed to find an effective method to improve the bioavailability of poorly soluble natural compounds, and explore the action mechanisms of them to promote their application.In this study, ORI-nicotinamide (NCT) cocrystal was successfully prepared for the first time to overcome the defects of ORI. The solubility and oral bioavailability of cocrystal (COC) increased 1.34 and 1.18 times compared with ORI. Moreover, MTT assay was applied to compare the cytotoxicity of positive control drug sorafenib with ORI and COC. The IC50 values of sorafenib, ORI and COC on HepG2 cells were 7.61, 8.79 and 7.36 nmol·mL-1, which indicated that the cytotoxicity of ORI could be enhanced by cocrystal preparation. The cellular metabolomics was innovatively introduced to gain insight into the difference of cytotoxicity mechanism between ORI and COC. The results showed that there were 78 metabolites with significant differences in content between the two groups, while these differential metabolites were related to 11 metabolic pathways. Among these, glycerophospholipid metabolism and cysteine and methionine metabolism were the significant differential pathways, and the downregulation of PC(14:0/16:1(9z)) and upregulation of homocysteine were the likely main reasons for higher cytotoxicity of COC.This study has presented novel approaches for enhancing the bioavailability and drug efficacy of natural compounds, while also offering fresh insights into the underlying action mechanisms of pharmaceutical cocrystals.Copyright © 2023 Elsevier GmbH. All rights reserved.