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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

ABSTRACT

Purpose

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.

Methods

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

Results

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.

Conclusion

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.

KEY WORDS

Drug interaction Grapefruit juice Intestinal absorption Multiple binding sites OATP2B1 

ABBREVIATIONS

AJ

Apple juice

GFJ

Grapefruit juice

LC/MS/MS

Liquid chromatography-tandem mass spectrometry

MBS

Multiple binding sites

OATP

Organic anion transporting polypeptide

OJ

Orange juice

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

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).

REFERENCES

  1. 1.
    Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158(3):693–705.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Kato K, Shirasaka Y, Kuraoka E, Kikuchi A, Iguchi M, Suzuki H, et al. Intestinal absorption mechanism of tebipenem pivoxil, a novel oral carbapenem: involvement of human OATP family in apical membrane transport. Mol Pharm. 2010;7(5):1747–56.PubMedCrossRefGoogle Scholar
  3. 3.
    Kobayashi D, Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I. Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane. J Pharmacol Exp Ther. 2003;306(2):703–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I. Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther. 2004;308(2):438–45.PubMedCrossRefGoogle Scholar
  5. 5.
    Glaeser H, Bailey DG, Dresser GK, Gregor JC, Schwarz UI, McGrath JS, et al. Intestinal drug transporter expression and the impact of grapefruit juice in humans. Clin Pharmacol Ther. 2007;81(3):362–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Shirasaka Y, Li Y, Shibue Y, Kuraoka E, Spahn-Langguth H, Kato Y, et al. Concentration-dependent effect of naringin on intestinal absorption of β1-adrenoceptor antagonist talinolol mediated by P-glycoprotein and organic anion transporting polypeptide (Oatp). Pharm Res. 2009;26(3):560–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Shirasaka Y, Kuraoka E, Spahn-Langguth H, Nakanishi T, Langguth P, Tamai I. Species difference in the effect of grapefruit juice on intestinal absorption of talinolol between human and rat. J Pharmacol Exp Ther. 2010;332(1):181–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Arakawa H, Shirasaka Y, Haga M, Nakanishi T, Tamai I. Active intestinal absorption of fluoroquinolone antibacterial agent ciprofloxacin by organic anion transporting polypeptide, Oatp1a5. Biopharm Drug Dispos. 2012;33(6):332–41.PubMedCrossRefGoogle Scholar
  9. 9.
    Tamai I. Oral drug delivery utilizing intestinal OATP transporters. Adv Drug Deliv Rev. 2012;64:508–14.PubMedCrossRefGoogle Scholar
  10. 10.
    Shirasaka Y, Suzuki K, Nakanishi T, Tamai I. Intestinal absorption of HMG-CoA reductase inhibitor pravastatin mediated by organic anion transporting polypeptide. Pharm Res. 2010;27(10):2141–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Ieiri I, Doi Y, Maeda K, Sasaki T, Kimura M, Hirota T, et al. Microdosing Clinical Study: Pharmacokinetic, pharmacogenomic (SLCO2B1), and interaction (grapefruit juice) profiles of celiprolol following the oral microdose and therapeutic dose. J Clin Pharmacol. 2011;52(7):1078–89.PubMedCrossRefGoogle Scholar
  12. 12.
    Imanaga J, Kotegawa T, Imai H, Tsutsumi K, Yoshizato T, Ohyama T, et al. The effects of the SLCO2B1 c.1457C > T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans. Pharmacogenet Genomics. 2011;21(2):84–93.PubMedCrossRefGoogle Scholar
  13. 13.
    Mougey EB, Lang JE, Wen X, Lima JJ. Effect of citrus juice and SLCO2B1 genotype on the pharmacokinetics of montelukast. J Clin Pharmacol. 2011;51(5):751–60.PubMedCrossRefGoogle Scholar
  14. 14.
    Shirasaka Y, Suzuki K, Shichiri M, Nakanishi T, Tamai I. Intestinal absorption of HMG-CoA reductase inhibitor pitavastatin mediated by organic anion transporting polypeptide and P-glycoprotein/multidrug resistance 1. Drug Metab Pharmacokinet. 2011;26(2):171–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Shirasaka Y, Suzuki K, Nakanishi T, Tamai I. Differential effect of grapefruit juice on intestinal absorption of statins due to inhibition of organic anion transporting polypeptide and/or P-glycoprotein. J Pharm Sci. 2011;100(9):3843–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Varma MV, Rotter CJ, Chupka J, Whalen KM, Duignan DB, Feng B, et al. pH-sensitive interaction of HMG-CoA reductase inhibitors (statins) with organic anion transporting polypeptide 2B1. Mol Pharm. 2011;8(4):1303–13.PubMedCrossRefGoogle Scholar
  17. 17.
    Dresser GK, Bailey DG, Leake BF, Schwarz UI, Dawson PA, Freeman DJ, et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther. 2002;71(1):11–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Schwarz UI, Seemann D, Oertel R, Miehlke S, Kuhlisch E, Fromm MF, et al. Grapefruit juice ingestion significantly reduces talinolol bioavailability. Clin Pharmacol Ther. 2005;77(4):291–301.PubMedCrossRefGoogle Scholar
  19. 19.
    Lilja JJ, Backman JT, Laitila J, Luurila H, Neuvonen PJ. Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol. Clin Pharmacol Ther. 2003;73(3):192–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Tapaninen T, Neuvonen PJ, Niemi M. Grapefruit juice greatly reduces the plasma concentrations of the OATP2B1 and CYP3A4 substrate aliskiren. Clin Pharmacol Ther. 2010;88(3):339–42.PubMedCrossRefGoogle Scholar
  21. 21.
    Dresser GK, Bailey DG. The effects of fruit juices on drug disposition: a new model for drug interactions. Eur J Clin Invest. 2003;33 Suppl 2:10–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Lilja JJ, Juntti-Patinen L, Neuvonen PJ. Orange juice substantially reduces the bioavailability of the beta-adrenergic-blocking agent celiprolol. Clin Pharmacol Ther. 2004;75(3):184–90.PubMedCrossRefGoogle Scholar
  23. 23.
    Lilja JJ, Raaska K, Neuvonen PJ. Effects of orange juice on the pharmacokinetics of atenolol. Eur J Clin Pharmacol. 2005;61(5–6):337–40.PubMedGoogle Scholar
  24. 24.
    Tapaninen T, Neuvonen PJ, Niemi M. Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren. Br J Clin Pharmacol. 2011;71(5):718–26.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Jeon H, Jang IJ, Lee S, Ohashi K, Kotegawa T, Ieiri I, et al. Apple juice greatly reduces systemic exposure to atenolol. Br J Clin Pharmacol. 2013;75(1):172–9.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Shirasaka Y, Shichiri M, Mori T, Nakanishi T, Tamai I. Major active components in grapefruit, orange, and apple juices responsible for OATP2B1-mediated drug interactions. J Pharm Sci. 2013;102(1):280–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Shirasaka Y, Shichiri M, Murata Y, Mori T, Nakanishi T, Tamai I. Long-lasting inhibitory effect of apple and orange juices, but not grapefruit juice, on OATP2B1-mediated drug absorption. Drug Metab Dispos. 2013;41(3):615–21.PubMedCrossRefGoogle Scholar
  28. 28.
    Greenblatt DJ. Analysis of drug interactions involving fruit beverages and organic anion-transporting polypeptides. J Clin Pharmacol. 2009;49(12):1403–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Satoh H, Yamashita F, Tsujimoto M, Murakami H, Koyabu N, Ohtani H, et al. Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos. 2005;33(4):518–23.PubMedCrossRefGoogle Scholar
  30. 30.
    Shirasaka Y, Mori T, Shichiri M, Nakanishi T, Tamai I. Functional pleiotropy of organic anion transporting polypeptide OATP2B1 due to multiple binding sites. Drug Metab Pharmacokinet. 2012;27(3):360–4.PubMedGoogle Scholar
  31. 31.
    Yamaoka K, Tanigawara Y, Nakagawa T, Uno T. A pharmacokinetic analysis program (multi) for microcomputer. J Pharmacobiodyn. 1981;4(11):879–85.PubMedCrossRefGoogle Scholar
  32. 32.
    Ludden TM, Beal SL, Sheiner LB. Comparison of the Akaike Information Criterion, the Schwarz criterion and the F test as guides to model selection. J Pharmacokinet Biopharm. 1994;22(5):431–45.PubMedCrossRefGoogle Scholar
  33. 33.
    Lilja JJ, Kivistö KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther. 1999;66(2):118–27.PubMedCrossRefGoogle Scholar

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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