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Phytochemistry Reviews

, Volume 14, Issue 2, pp 233–272 | Cite as

Flavonoid compounds as reversal agents of the P-glycoprotein-mediated multidrug resistance: biology, chemistry and pharmacology

  • Ana Ferreira
  • Sarah Pousinho
  • Ana Fortuna
  • Amílcar Falcão
  • Gilberto Alves
Article

Abstract

Multidrug resistance (MDR) represents one of the major problems in pharmacotherapy of important diseases (e.g., cancer, epilepsy). Although many factors may contribute to the development of MDR phenotype, the increased expression and/or functional activity of P-glycoprotein (P-gp; active drug efflux transporter) across the cell membrane has been recognized as the main one. Therefore, a great attention has been given to the search of P-gp inhibitors as therapeutic agents to reverse the MDR mediated by P-gp. Since the chemical entities identified over the last three decades as potential P-gp inhibitors did not show suitable pharmacological properties, more recently herbal components, such as flavonoid compounds, have gained a great interest as safe P-gp inhibitors. The interest in flavonoids as P-gp inhibitors is increasing due to their potential favourable characteristics, including selectivity and non-cytotoxic effects. Flavonoids integrate the third-generation non-pharmaceutical category of P-gp inhibitors, and some of them exhibited effects comparable to those of the classic P-gp inhibitors. In fact, some flavonoids found in foods and beverages of herbal origin appear to be quite promising to inhibit the P-gp–mediated drug efflux, indicating their potential value to enhance the systemic/cellular bioavailability of P-gp drug substrates when administrated in co-therapy. This review paper summarizes the current evidence of P-gp inhibitory effects produced by flavonoids, taking into account studies performed in cell-based in vitro models, in vivo animal models and clinical trials.

Keywords

Flavonoids P-glycoprotein inhibition Drug efflux Multidrug resistance 

Abbreviations

ABC

Adenosine triphosphate (ATP)-binding cassette

AUC

Area under the concentration–time curve

BCRP

Breast cancer resistance protein

Clt

Total body clearance

Cmax

Peak concentration

CNS

Central nervous system

CYP

Cytochrome P450

IV

Intravenous

MDR

Multidrug resistance

MRP

Multidrug resistance-associated protein

NBD

Nucleotide-binding domain

P-gp

P-glycoprotein

TMs

Transmembrane α-helix segments

TMD

Transmembrane domain

Notes

Acknowledgments

The authors thank the support of Fundação para a Ciência e a Tecnologia (FCT, Portugal) through the fellowship SFHR/BD/84936/2012, involving the POPH—QREN which is co-funded by FSE and MEC. The authors also thank the funding through the Strategic Project PEst-C/SAU/UI0709/2011.

Conflict of interest

The authors have declared no conflict of interest.

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Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Ana Ferreira
    • 1
    • 2
  • Sarah Pousinho
    • 1
  • Ana Fortuna
    • 2
    • 3
  • Amílcar Falcão
    • 2
    • 3
  • Gilberto Alves
    • 1
    • 2
  1. 1.CICS-UBI – Health Sciences Research CentreUniversity of Beira InteriorCovilhãPortugal
  2. 2.CNC – Centre for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal
  3. 3.Laboratory of Pharmacology, Faculty of PharmacyUniversity of CoimbraCoimbraPortugal

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