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In Vivo Exposure of Kaempferol Is Driven by Phase II Metabolic Enzymes and Efflux Transporters

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Abstract

Kaempferol is a well-known flavonoid; however, it lacks extensive pharmacokinetic studies. Phase II metabolic enzymes and efflux transporters play an important role in the disposition of flavonoids. This study aimed to investigate the mechanism by which phase II metabolic enzymes and efflux transporters determine the in vivo exposure of kaempferol. Pharmacokinetic analysis in Sprague–Dawley rats revealed that kaempferol was mostly biotransformed to conjugates, namely, kaempferol-3-glucuronide (K-3-G), kaempferol-7-glucuronide (K-7-G), and kaempferol-7-sulfate, in plasma. K-3-G represented the major metabolite. Compared with that in wild-type mice, pharmacokinetics in knockout FVB mice demonstrated that the absence of multidrug resistance protein 2 (MRP2) and breast cancer resistance protein (BCRP) significantly increased the area under the curve (AUC) of the conjugates. The lack of MRP1 resulted in a much lower AUC of the conjugates. Intestinal perfusion in rats revealed that the glucuronide conjugates were mainly excreted in the small intestine, but 7-sulfate was mainly excreted in the colon. In Caco-2 monolayers, K-7-G efflux toward the apical (AP) side was significantly higher than K-3-G efflux. In contrast, K-3-G efflux toward the basolateral (BL) side was significantly higher than K-7-G efflux. The BL-to-AP efflux was significantly reduced in the presence of the MRP2 inhibitor LTC4. The AP-to-BL efflux was significantly decreased in the presence of the BL-side MRPs inhibitor MK571. The BCRP inhibitor Ko143 decreased the glucuronide conjugate efflux. Therefore, kaempferol is mainly exposed as K-3-G in vivo, which is driven by phase II metabolic enzymes and efflux transporters (i.e., BCRP and MRPs).

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Acknowledgments

This work was supported by the grants of National Natural Science Foundation of China (81120108025 and 81503466), Science and Technology Project of Guangzhou City (201509010004) and Guangdong Natural Science Foundation Province (2015AD030312012).

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    Authors and Affiliations

    1. Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China

      Liang Zheng, Jian Shi, Yunli Tong, Yuting Liu & Zhongqiu Liu

    2. International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People’s Republic of China

      Liang Zheng, Lijun Zhu, Min Zhao, Jian Shi, Yuhuan Li, Jia Yu, Huangyu Jiang, Jinjun Wu, Yunli Tong, Yuting Liu, Ming Hu, Linlin Lu & Zhongqiu Liu

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

      Ming Hu

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    Liang Zheng and Lijun Zhu contributed equally to this work.

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    Zheng, L., Zhu, L., Zhao, M. et al. In Vivo Exposure of Kaempferol Is Driven by Phase II Metabolic Enzymes and Efflux Transporters. AAPS J 18, 1289–1299 (2016). https://doi.org/10.1208/s12248-016-9951-9

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