Pharmaceutical Research

, Volume 31, Issue 8, pp 2035–2043 | Cite as

Substrate- and Dose-Dependent Drug Interactions with Grapefruit Juice Caused by Multiple Binding Sites on OATP2B1

  • Yoshiyuki Shirasaka
  • Takanori Mori
  • Yukiko Murata
  • Takeo Nakanishi
  • Ikumi TamaiEmail author
Research Paper



OATP2B1-mediated grapefruit juice (GFJ)-drug interactions are substrate-dependent; for example, GFJ ingestion significantly reduces bioavailability of fexofenadine, but not pravastatin. In the present study, we aimed to establish whether this observation can be explained by the presence of multiple binding sites (MBS) on OATP2B1.


OATP2B1-mediated drug uptake was evaluated using a Xenopus oocyte expression system. Drug concentration was quantified by LC/MS/MS analysis.


OATP2B1-mediated uptake of pravastatin and fexofenadine exhibited biphasic saturation kinetics, indicating the presence of MBS on OATP2B1. GFJ strongly inhibited pravastatin uptake mediated by the high-affinity site on OATP2B1, while no significant inhibition of the low-affinity site was observed. In contrast, high-affinity transport of fexofenadine was only modestly inhibited by GFJ, while significant inhibition of the low-affinity site was observed. Contribution analysis indicated that both drugs are transported via the low-affinity site on OATP2B1 at therapeutically relevant concentrations. These findings indicate that only fexofenadine is expected to interact with GFJ on OATP2B1 at therapeutic concentrations, in accordance with the clinical observations.


Substrate- and dose-dependent GFJ-drug interactions mediated by OATP2B1 might be explained in terms of the presence of MBS: interaction occurs only when drug and GFJ components share the same binding site on OATP2B1.


Drug interaction Grapefruit juice Intestinal absorption Multiple binding sites OATP2B1 



Apple juice


Grapefruit juice


Liquid chromatography-tandem mass spectrometry


Multiple binding sites


Organic anion transporting polypeptide


Orange juice



This work was supported in part by a Grant-in-Aid for Scientific Research [Research Project Number: 21790147] and a JSPS Postdoctoral Fellowship for Research Abroad [Research Project Number: H23-694] from the Japan Society for the Promotion of Science (JSPS).


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Yoshiyuki Shirasaka
    • 1
  • Takanori Mori
    • 1
  • Yukiko Murata
    • 1
  • Takeo Nakanishi
    • 1
  • Ikumi Tamai
    • 1
    Email author
  1. 1.Faculty of Pharmaceutical Sciences Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan

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