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Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Regulate the Disposition of Acacetin Glucuronides

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Abstract

Purpose

To determine the mechanism responsible for acacetin glucuronide transport and the bioavailability of acacetin.

Methods

Area under the curve (AUC), clearance (CL), half-life (T1/2) and other pharmacokinetic parameters were determined by the pharmacokinetic model. The excretion of acacetin glucuronides was evaluated by the mouse intestinal perfusion model and the Caco-2 cell model.

Results

In pharmacokinetic studies, the bioavailability of acacetin in FVB mice was 1.3%. Acacetin was mostly exposed as acacetin glucuronides in plasma. AUC of acacetin-7-glucuronide (Aca-7-Glu) was 2-fold and 6-fold higher in Bcrp1 (−/−) mice and Mrp2 (−/−) mice, respectively. AUC of acacetin-5-glucuronide (Aca-5-Glu) was 2-fold higher in Bcrp1 (−/−) mice. In mouse intestinal perfusion, the excretion of Aca-7-Glu was decreased by 1-fold and 2-fold in Bcrp1 (−/−) and Mrp2 (−/−) mice, respectively. In Caco-2 cells, the efflux rates of Aca-7-Glu and Aca-5-Glu were significantly decreased by breast cancer resistance protein (BCRP) inhibitor Ko143 and multidrug resistance protein 2 (MRP2) inhibitor LTC4. The use of these inhibitors markedly increased the intracellular acacetin glucuronide content.

Conclusions

BCRP and MRP2 regulated the in vivo disposition of acacetin glucuronides. The coupling of glucuronidation and efflux transport was probably the primary reason for the low bioavailability of acacetin.

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Abbreviations

AP:

Apical

AUC:

Area under the curve

BCRP:

Breast cancer resistance protein

BL:

Basolateral

Cmax :

Maximum plasma concentration

CL:

Clearance

HBSS:

Hanks’ balanced salts

HPLC:

High performance liquid chromatography

HRMS:

High-resolution mass spectra

LLOQ:

Lower limit of quantification

MRP:

Multidrug resistance protein

MRT:

Mean residence time

T1/2 :

Half-life

UGT:

Uridine 5′-diphospho-glucuronosyltransferases

UHPLC-MS/MS:

Ultra high performance liquid chromatography/tandem mass spectrometry

UV:

Ultraviolet and visible spectrum

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Acknowledgments and Disclosures

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

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Authors and Affiliations

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

    Huangyu Jiang, Jia Yu, Haihui Zheng, Jiamei Chen, Jinjun Wu, Xiaoxiao Qi, Ying Wang, Ming Hu, Lijun Zhu & Zhongqiu Liu

  2. First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, 832008, China

    Xinchun Wang

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

    Ming Hu

  4. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR), China

    Zhongqiu Liu

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  1. Huangyu Jiang
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Correspondence to Lijun Zhu or Zhongqiu Liu.

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Jiang, H., Yu, J., Zheng, H. et al. Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Regulate the Disposition of Acacetin Glucuronides. Pharm Res 34, 1402–1415 (2017). https://doi.org/10.1007/s11095-017-2157-8

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  • DOI: https://doi.org/10.1007/s11095-017-2157-8

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