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Effects of red ginseng extract on the pharmacokinetics and disposition of warfarin via intestinal Cyp2c11 modulation in rats

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Abstract

Purpose

This study aimed to develop and validate the analytical method for warfarin and its major metabolite 7-hydroxy warfarin using liquid chromatography–triple quadrupole mass spectrometry (LC–MS/MS) as well as to conduct pharmacokinetic and elimination studies on warfarin in rats.

Methods

The LC–MS/MS analytical method for warfarin and 7-hydroxy warfarin was used and validated. Mice were administered warfarin (1 mg/kg) with or without the coadministration of Korean red ginseng extract (RGE, 2 g/kg/day) once or multiple times for 7 days. Thereafter, the pharmacokinetics and disposition of warfarin and 7-hydroxy warfarin were measured. The underlying mechanisms of their pharmacokinetic alterations were observed by measuring Cyp2c11 expression in the intestine and liver and by investigating the inhibitory effects of RGE and ginsenoside Rb1 on warfarin metabolism in rat intestinal and liver microsomes.

Results

We demonstrated good linearity in a range of 20–15,000 ng/mL for warfarin and 1–500 ng/mL for 7-hydroxy warfarin by using liquid-liquid extraction with ethyl acetate. The analytical method for this study is more reliable for conducting pharmacokinetic and elimination studies with acceptable accuracy, precision, recovery, and matrix effect. During the RGE treatment, warfarin concentration increased and the metabolic activity from warfarin to 7-hydroxy warfarin decreased in rats. Moreover, RGE treatment decreased the protein expression of Cyp2c11, the responsible metabolizing enzyme of warfarin, in rat intestine but not the liver. Ginsenoside Rb1, the most abundant ginsenoside in RGE, also inhibited the metabolic activity of Cyp2c11 in the intestine but not in the liver.

Conclusion

The herb–drug interactions between RGE and warfarin occurred via intestinal Cyp2c11 inhibition (for single administration of RGE) as well as decreased intestinal Cyp2c11 expression (for repeated administration of RGE) in rats.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2020R1I1A3074384 and NRF-2020R1A5A2017323).

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Authors and Affiliations

  1. College of Pharmacy, Dankook University, Cheon-an, 31116, Republic of Korea

    So Yeon Jeon & Min-Koo Choi

  2. BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea

    Jin-Hyang Park, Mi Jeong Kwon & Im-Sook Song

  3. College of Pharmacy, Kyungpook National University, Daegu, 41566, Korea

    Im-Sook Song

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  1. So Yeon Jeon
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Correspondence to Min-Koo Choi or Im-Sook Song.

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All authors (S.Y. Jeon, J.H. Park, M.J. Kwon, M.K. Choi, and I.S. Song) declare that they have no conflict of interest.

Research involving human or animal participants

All animal procedures were approved by the Animal Care and Use Committee of Kyungpook National University (Approval No. 2017-0044) and were carried out according to the National Institutes of Health guidelines for the care and the use of laboratory animals.

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Jeon, S.Y., Park, JH., Kwon, M.J. et al. Effects of red ginseng extract on the pharmacokinetics and disposition of warfarin via intestinal Cyp2c11 modulation in rats. J. Pharm. Investig. 54, 85–97 (2024). https://doi.org/10.1007/s40005-023-00650-x

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