The bioavailability enhancement and insight into the action mechanism of poorly soluble natural compounds from co-crystals preparation: Oridonin as an example.

Background: 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.

Objective: 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.

Results: 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 IC values of sorafenib, ORI and COC on HepG2 cells were 7.61, 8.79 and 7.36 nmol·mL, 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.

Conclusions: 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.