2. Academic Validation
  3. Inhibitory effects of flavonoids on P-glycoprotein in vitro and in vivo: Food/herb-drug interactions and structure-activity relationships

Inhibitory effects of flavonoids on P-glycoprotein in vitro and in vivo: Food/herb-drug interactions and structure-activity relationships

  • Toxicol Appl Pharmacol. 2019 Apr 15;369:49-59. doi: 10.1016/j.taap.2019.02.010.
Jie Bai 1,  Shengyu Zhao 2,  Xiaoqing Fan 3,  Yonghui Chen 4,  Xiaowen Zou 5,  Minwan Hu 6,  Baolian Wang 7,  Jing Jin 8,  Xiaojian Wang 9,  Jinping Hu 10,  Dan Zhang 11,  Yan Li 12
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: baijie@imm.ac.cn.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: zhaoshengyu@imm.ac.cn.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: fanxiaoqing@imm.ac.cn.
  • 4 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: chenyonghui@imm.ac.cn.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: zouxiaowen@imm.ac.cn.
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: huminwan@imm.ac.cn.
  • 7 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: wangbaolian@imm.ac.cn.
  • 8 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: rebeccagold@imm.ac.cn.
  • 9 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: wangxiaojian@imm.ac.cn.
  • 10 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: hujp@imm.ac.cn.
  • 11 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: danzhang@imm.ac.cn.
  • 12 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. Electronic address: yanli@imm.ac.cn.
PMID: 30790579 DOI: 10.1016/j.taap.2019.02.010
Abstract

Flavonoids are a class of polyphenol antioxygen, despite various known biological activities and therapeutic potential, scattered but not much is known about their interactions with drug transporters. P-glycoprotein (P-gp) as a cellular defense mechanism by effluxing its substrates has been widely investigated. The aim of this study was to investigate the inhibitory effects of 75 Flavonoids on P-gp in vitro and in vivo and to illuminate the structure-activity relationships of Flavonoids with P-gp. Five Flavonoids, including tangeretin, sinensetin, isosinensetin, sciadopitysin and oroxylin A exhibited significant inhibition on P-gp in MDR1-MDCKIIcells, which reduced the P-gp-mediated efflux of paraquat and taxol and consequently increased their cell toxicity. In addition, co-administration of digoxin with five Flavonoids increased the AUC0-t of digoxin in different extents in rats, from 19.84% to 81.51%. Molecular docking assays elucidated the inhibitory effect of Flavonoids might be related to Pi interactions, but not hydrogen bonds. The pharmacophore model suggested the hydrophobic groups in B benzene ring may play a vital role in the potency of Flavonoids inhibition on P-gp. Taken together, our findings would provide the basis for a reliable assessment of the potential risks of flavonoid-containing food/herb-drug interactions in humans.

Keywords

Flavonoids; Inhibition; P-glycoprotein; Structure–activity relationships.

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