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Effects and Mechanism of Action of Panax notoginseng Saponins on the Pharmacokinetics of Warfarin

  • Original Research Article
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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

A Correction to this article was published on 22 February 2022

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Abstract

Backgroud

The interactions between Chinese herbs and drugs pose a great challenge to the combined clinical application of Chinese herbs and drugs. Chinese medicinal products contain complex pharmacologically active components that may influence the in vivo processes of drugs in a variety of ways. In China, drugs based on Panax ginseng total saponins (PNS) are often combined with warfarin for the treatment of cardiovascular diseases.

Objectives

To assess the effects of Panax notoginseng saponins (PNS) on the pharmacokinetics of warfarin and its mechanism.

Method

Blood was collected for the determination of the prothrombin time (PT) and international normalized ratio (INR) from rats treated with warfarin alone or with warfarin + PNS. The plasma concentration of warfarin was determined by high-performance liquid chromatography. Western blot was used to detect the expression of cytochrome P450 (CYP) enzymes.

Results

When warfarin and PNS were co-administered, the PT and INR increased compared to when warfarin was given alone. 72 hours after administration, compared to the warfarin alone group, the warfarin + low-dose PNS, warfarin + medium-dose PNS, and warfarin + high-dose PNS groups showed 110%, 122%, and 126% increases in PT, respectively (all P < 0.05), as well as 111%, 124%, and 128% increases in INR (all P < 0.05). Compared with the warfarin alone group, the clearance rate (CL/F) of warfarin in the warfarin + low-dose PNS, warfarin + medium-dose PNS, and warfarin + high-dose PNS groups was 10% (P  > 0.05), 23% (P  < 0.05), and 33% (P  < 0.05) lower, respectively, while the systemic exposure (area under the concentration-time curve, AUC0–t) increased by 106% (P  > 0.05), 119% (P  < 0.05), and 134% (P  < 0.05), respectively, and the blood concentration of warfarin incresed by 112%, 113%, and 114%, respectively (all P > 0.05). After combined treatment of HepG2 cells with warfarin + PNS, CYP1A2 expression was upregulated (P  < 0.05) and CYP3A4 was downregulated (P  < 0.05) but there was no effect on CYP2C9. In animal experiments, PNS had different effect on the expression of CYP1A2 in different doses. While a low dose of PNS resulted in downregulated CYP1A2 expression (P  < 0.05), a medium dose resulted in upregulation (P  < 0.05), and CYP1A2 expression was not significantly affected by a high dose of PNS (P  > 0.05). Meanwhile, PNS at all doses downregulated the expression of CYP3A4 (P  < 0.05) but had no effect on the expression of CYP2C9 (P >  0.05).

Conclusion

PNS can increase the blood concentration of warfarin, as well as the exposure time, and it can enhance the anticoagulant effect of warfarin by inhibiting the expression of the liver enzyme CYP3A4.

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Acknowledgements

The authors wish to thank Mrs. Tingting Wu regarding the collection of the data.

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Authors and Affiliations

  1. Department of Pharmacy, Fujian Medical University Union Hospital, #29 Xinquan Road, Fuzhou, 350001, Fujian, China

    Jiafen Qian, Wenjun Chen, Jianmei Wu, Meina Lv, Shaojun Jiang, Zhiwei Zeng, Zongwei Fang, Mingrong Chen & Jinhua Zhang

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  1. Jiafen Qian
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Correspondence to Jinhua Zhang.

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Funding

This study was funded by Fujian Provincial Health Technology Project, China (2019-CX-19).

Conflicts of interest

The authors declare that there are no conflicts of interest.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Author contributions

WJC, JMW, and JFQ, who participated in the design and conduct of the study, contributed equally to the article. MNL, SJJ, ZWZ, ZWF, and MRC analyzed the data and conducted the section on statistical analysis, and JHZ revised the manuscript. All the authors contributed to the final paper.

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The protocol of the study was reviewed and approved by the Ethics Committee of Fujian Medical University. All institutional and national guidelines for the care of the laboratory animals were followed.

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Qian, J., Chen, W., Wu, J. et al. Effects and Mechanism of Action of Panax notoginseng Saponins on the Pharmacokinetics of Warfarin. Eur J Drug Metab Pharmacokinet 47, 331–342 (2022). https://doi.org/10.1007/s13318-022-00753-0

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