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Triple Recycling Processes Impact Systemic and Local Bioavailability of Orally Administered Flavonoids

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Abstract

Triple recycling (i.e., enterohepatic, enteric and local recycling) plays a central role in governing the disposition of phenolics such as flavonoids, resulting in low systemic bioavailability but higher gut bioavailability and longer than expected apparent half-life. The present study aims to investigate the coexistence of these recycling schemes using model bioactive flavonoid tilianin and a four-site perfused rat intestinal model in the presence or absence of a lactase phlorizin hydrolase (LPH) inhibitor gluconolactone and/or a glucuronidase inhibitor saccharolactone. The result showed that tilianin could be metabolized into tilianin glucuronide, acacetin, and acacetin glucuronide, which are excreted into the bile and luminal perfusate (highest in the duodenum and lowest in the colon). Gluconolactone (20 mM) significantly reduced the absorption of tilianin and the enteric and biliary excretion of acacetin glucuronide. Saccharolactone (0.1 mM) alone or in combination of gluconolactone also remarkably reduced the biliary and intestinal excretion of acacetin glucuronide. Acacetin glucuronides from bile or perfusate were rapidly hydrolyzed by bacterial β-glucuronidases to acacetin, enabling enterohepatic and enteric recycling. Moreover, saccharolactone-sensitive tilianin disposition and glucuronide deconjugation, which was more active in the small intestine than the colon, points to the small intestinal origin of the deconjugation enzyme and supports the presence of local recycling scheme. In conclusion, our studies have demonstrated triple recycling of a bioactive phenolic (i.e., a model flavonoid), and this recycling may have an impact on the site and duration of polyphenols pharmacokinetics in vivo.

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Acknowledgments

This work was supported by the Key Projects of National Natural Science Foundation of China (81120108025 and U1203204). MH was also supported by National Institute of Health Grant Number GM070737.

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    Authors and Affiliations

    1. International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China

      Peimin Dai, Lijun Zhu, Feifei Luo, Linlin Lu, Qiang Li, Liping Wang, Ying Wang, Ming Hu & Zhongqiu Liu

    2. Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China

      Peimin Dai, Qiang Li, Ying Wang & Zhongqiu Liu

    3. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 1441 Moursund Street, Houston, TX, 77030, USA

      Ming Hu

    4. First Affiliated Hospital of the Medical College, Shihezi University, Xin Jiang, 832008, China

      Liping Wang & Xinchun Wang

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    Correspondence to Ming Hu or Zhongqiu Liu.

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    Guangzhou University of Chinese Medicine and Southern Medical University contributed equally to this paper.

    Peimin Dai and Lijun Zhu contributed equally to this work.

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    Dai, P., Zhu, L., Luo, F. et al. Triple Recycling Processes Impact Systemic and Local Bioavailability of Orally Administered Flavonoids. AAPS J 17, 723–736 (2015). https://doi.org/10.1208/s12248-015-9732-x

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    • DOI: https://doi.org/10.1208/s12248-015-9732-x

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