Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase

Hang Yu; Hui Xu; Xinyu Yang; Zhengwei Zhang; Jiachun Hu; Jinyue Lu; Jie Fu; Mengmeng Bu; Haojian Zhang; Zhao Zhai; Jingyue Wang; Jiandong Jiang; Yan Wang

doi:10.1016/j.jpha.2023.06.012

Volume 13 Issue 9

Sep. 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(9): 1024-1040

Hang Yu, Hui Xu, Xinyu Yang, Zhengwei Zhang, Jiachun Hu, Jinyue Lu, Jie Fu, Mengmeng Bu, Haojian Zhang, Zhao Zhai, Jingyue Wang, Jiandong Jiang, Yan Wang. Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase[J]. Journal of Pharmaceutical Analysis, 2023, 13(9): 1024-1040. doi: 10.1016/j.jpha.2023.06.012

Citation:

Hang Yu, Hui Xu, Xinyu Yang, Zhengwei Zhang, Jiachun Hu, Jinyue Lu, Jie Fu, Mengmeng Bu, Haojian Zhang, Zhao Zhai, Jingyue Wang, Jiandong Jiang, Yan Wang. Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase[J]. Journal of Pharmaceutical Analysis, 2023, 13(9): 1024-1040. doi: 10.1016/j.jpha.2023.06.012

Citation:

Hang Yu, Hui Xu, Xinyu Yang, Zhengwei Zhang, Jiachun Hu, Jinyue Lu, Jie Fu, Mengmeng Bu, Haojian Zhang, Zhao Zhai, Jingyue Wang, Jiandong Jiang, Yan Wang. Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase[J]. Journal of Pharmaceutical Analysis, 2023, 13(9): 1024-1040. doi: 10.1016/j.jpha.2023.06.012

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Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase

doi: 10.1016/j.jpha.2023.06.012

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, 100050, China

Funds:

This project was supported by the National Key R&D Program of China (Grant No.: 2022YFA0806400), the CAMS Innovation Fund for Medical Sciences (Grant Nos.: 2022-I2M-1-028, 2022-I2M-2-002, and 2021-I2M-1-007), the National Natural Science Foundation of China (Grant Nos.: 81973290 and 82173888), and Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, China (Grant No.: Z141102004414062). We would like to thank Shimadzu (China) Co., Ltd. for technological support.

Received Date: Feb. 12, 2023
Accepted Date: Jun. 25, 2023
Rev Recd Date: Jun. 15, 2023
Publish Date: Jun. 28, 2023

Abstract

Abstract

Specnuezhenide (SNZ) is among the main components of Fructus Ligustri Lucidi, which has anti-inflammation, anti-oxidation, and anti-tumor effect. The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ. In this study, the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored. SNZ can be rapidly metabolized by the gut microbiome, and two intestinal bacterial metabolites of SNZ, salidroside and tyrosol, were discovered. In addition, carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism. At the same time, no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate, indicating that the gut microbiota is the main part involved in the metabolism of SNZ. In addition, pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota. Interestingly, tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ, which indicated that SNZ exhibited potential to inhibit tumor growth, and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues. At the same time, SNZ modulated the structure of gut microbiota and fungal group, which may be the mechanism governing the antitumoral activity of SNZ. Furthermore, SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo. In the future, targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.
- Specnuezhenide,
- Pharmacokinetics,
- Tumor,
- Gut microbiota,
- Fungi,
- Metabolism

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References(71)

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