Pharmaceutical Research

, Volume 26, Issue 2, pp 480–487

Curcumin Inhibits the Activity of ABCG2/BCRP1, a Multidrug Resistance-Linked ABC Drug Transporter in Mice

  • Suneet Shukla
  • Hani Zaher
  • Anika Hartz
  • Björn Bauer
  • Joseph A. Ware
  • Suresh V. Ambudkar
Research Paper

Abstract

Purpose

To evaluate the in vivo efficacy of curcumin as an inhibitor of the multidrug-resistance-linked ATP Binding Cassette (ABC) drug transporter, ABCG2.

Methods

Photoaffinity labeling with [125I]-iodoarylazidoprazosin was used to characterize the interaction of sulfasalazine, a substrate of the mouse ABCG2, with human ABCG2. In addition, the inhibitory effect of curcumin on ABCG2 was evaluated in brain capillaries from rats. Furthermore, the effect of curcumin on absorption of orally administered sulfasalazine in wild-type and abcg2−/− mice was also determined.

Results

Sulfasalazine interacted at the drug-substrate site(s) of human ABCG2. Curcumin inhibited ABCG2 activity at nanomolar concentrations at the rat blood-brain barrier in the ex vivo assay. Based on studies in wild type and abcg2−/− mice, we observed that oral curcumin increased Cmax and relative bioavailability of sulfasalazine by selectively inhibiting ABCG2 function.

Conclusions

This study validates our previous in vitro results with human ABCG2 (Chearwae et al., Mol. Cancer Ther. 5:1995–2006, 2006) and provides the first in vivo evidence for the inhibition by curcumin of ABCG2-mediated efflux of sulfasalazine in mice. Based on these studies, we propose that non-toxic concentrations of curcumin may be used to enhance drug exposure when the rate-limiting step of drug absorption and/or tissue distribution is impacted by ABCG2.

KEY WORDS

ABC transporter ABCG2 curcumin multidrug resistance sulfasalazine 

ABBREVIATIONS

ABC

ATP binding cassette

AUC

area under concentration-time curve

BBB

blood–brain barrier

IAAP

iodoarylazidoprazosin

MDR

multidrug resistance

P-gp

P-glycoprotein

SASP

sulfasalazine

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Suneet Shukla
    • 1
  • Hani Zaher
    • 2
    • 5
  • Anika Hartz
    • 3
  • Björn Bauer
    • 4
  • Joseph A. Ware
    • 2
    • 6
  • Suresh V. Ambudkar
    • 1
  1. 1.Laboratory of Cell Biology, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaUSA
  2. 2.Department of Pharmacokinetics, Dynamics, and MetabolismPfizer Global Research and DevelopmentAnn ArborUSA
  3. 3.Department of Biochemistry and Molecular Biochemistry, Medical SchoolUniversity of MinnesotaDuluthUSA
  4. 4.Department of Pharmaceutical Sciences, College of PharmacyUniversity of MinnesotaDuluthUSA
  5. 5.Drug Discovery SupportBoehringer Ingelheim Pharmaceuticals, Inc.RidgefieldUSA
  6. 6.Genentech Inc.South San FranciscoUSA

Personalised recommendations