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Pharmacokinetics and extensive intestinal first-pass effects of apigenin and its active metabolite, apigenin-7-O-glucuronide, in rats

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Abstract

Purpose

This study investigated the metabolism and pharmacokinetics of apigenin and its metabolite, apigenin-7-O-glucuronide (A7G), using a newly developed UPLC-MS/MS method.

Methods

A simple and sensitive UPLC-MS/MS method was developed for simultaneous quantification of apigenin and A7G, and their pharmacokinetic properties were examined using an in vivo rat model. Moreover, stability under various conditions, protein binding, blood distribution, and metabolic studies were performed in vitro.

Results

Apigenin showed poor stability in simulated intestinal fluid, whereas A7G was stable for 24 h. An in vivo pharmacokinetic study demonstrated that apigenin had a very low oral bioavailability (F) of 0.708% and was mainly metabolized to A7G. Notably, systemic exposure (Cmax and AUC) of apigenin after oral administration of A7G was markedly higher (2.62- and 14.3-fold, respectively) than that after oral administration of apigenin. Apigenin and A7G were significantly metabolized in both hepatic and intestinal S9 fractions. Based on the well-stirred and QGut model concepts, they were classified as compounds with low EH (0.0167–0.0389) and moderate-to-high EG (0.626–0.979) in rats, indicating that the intestine had a greater contribution than the liver to pre-systemic elimination of both phytochemicals.

Conclusion

The low F of apigenin could be attributed to its poor stability in the gastrointestinal lumen and extensive intestinal first-pass effect, which could be improved by oral administration of A7G, demonstrating the potential of A7G as a natural prodrug for improving the low F of apigenin.

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Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government (MSIT) (NRF-2023R1A2C1006010) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI23C0141).

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  1. Seong-Wook Seo, Soon Ho Choi and Jung-Ki Hong contributed equally to this work.

Authors and Affiliations

  1. Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Geumjeong-gu, Busan, 46241, Republic of Korea

    Seong-Wook Seo, Jung-Ki Hong & In-Soo Yoon

  2. Research Institute, APRG Inc, Yongin-si, Gyeonggi, 16950, Republic of Korea

    Soon Ho Choi

  3. Department of Oriental Medicine Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi, 17104, Republic of Korea

    Soon Ho Choi & Se Chan Kang

  4. Research Center, CureBio Therapeutics Co., Ltd., Suwon-si, Gyeonggi, 16229, Republic of Korea

    Kyoung Mi Kim

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  1. Seong-Wook Seo
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All authors (S.W. Seo, S.H. Choi, J.K. Hong, K.M. Kim, S.C. Kang and I.S. Yoon) declare that they have no conflict of interest.

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Animal studies were performed according to the protocol approved by Institutional Animal Care and Use Committee of Pusan National University (approval number: PNU-2023-3245; Busan, Republic of Korea).

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Seo, SW., Choi, S.H., Hong, JK. et al. Pharmacokinetics and extensive intestinal first-pass effects of apigenin and its active metabolite, apigenin-7-O-glucuronide, in rats. J. Pharm. Investig. (2024). https://doi.org/10.1007/s40005-024-00662-1

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