Pharmaceutical Research

, Volume 16, Issue 4, pp 478–485 | Cite as

Grapefruit Juice Activates P-Glycoprotein-Mediated Drug Transport

  • Andrea Soldner
  • Uwe Christians
  • Miki Susanto
  • Vincent J. Wacher
  • Jeffrey A. Silverman
  • Leslie Z. Benet


Purpose. Grapefruit juice (GJ) is known to increase the oral bioavailability of many CYP3A-substrates by inhibiting intestinal phase-I metabolism. However, the magnitude of AUC increase is often insignificant and highly variable. Since we earlier suggested that CYP3A and P-glycoprotein (P-gp) form a concerted barrier to drug absorption, we investigated the role of P-gp in GJ-drug interactions.

Methods. The transcellular bidirectional flux of drugs that are (i) CYP3A-and/or P-gp substrates (Vinblastine, Cyclosporine, Digoxin, Fexofenadine, Losartan) or that are (ii) primary CYP3A-substrates (Felodipine, Nifedipine) was evaluated across MDCK-MDR1 cell monolayers with or without GJ, verifying monolayer integrity at all times.

Results. While both apical-to-basal (A-B) and basal-to-apical (B-A) fluxes of all CYP3A/P-gp substrates tested were increased in the presence of GJ, the resulting net efflux (B-A/A-B) was in all cases significantly greater with GJ than control (Vin, 28.0 vs. 5.1; CsA, 9.9 vs. 2.8; Dig, 22. 9 vs. 14.7, Fex, 22.3 vs. 11.1, Los, 39.6 vs. 26). In contrast, no such GJ flux effect was observed with Pel and Nif, substrates of CYP3A only (2 vs. 1.7 and 1.2 vs. 1.3).

Conclusions. GJ significantly activates P-gp-mediated efflux of drugs that are substrates of P-gp, potentially partially counteracting the CYP3A-inhibitory effects of GJ.

grapefruit juice bioavailability active transport intestine cytochrome P450 3A metabolism 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    D. G. Bailey, J. D. Spence, C. Munoz, and J. M. O. Arnold. Interaction of citrus juices with felodipine and nifedipine. Lancet 337:268–269 (1991).Google Scholar
  2. 2.
    K. S. Lown, D. G. Bailey, R. J. Fontana, S. K. Janardan, C. H. Adair, L. A. Fortlage, M. B. Brown, W. Guo, and P. B. Watkins. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J. Clin. Invest. 99:2545–2553 (1997).Google Scholar
  3. 3.
    M. P. Ducharme, L. H. Warbasse, and D. J. Edwards. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin. Pharmacol. Ther. 57:485–491 (1995).Google Scholar
  4. 4.
    S. E. Rau, J. R. Bend, J. M. O. Arnold, L. T. Tran, J. D. Spence, and D. G. Bailey. Grapefruit juice-terfenadine single-dose interaction: Magnitude, mechanism, and relevance. Clin. Pharmacol. Ther. 61:401–409 (1997).Google Scholar
  5. 5.
    H. H. T. Kupferschmidt, K. E. Fattinger, H. R. Ha, F. Follath, and S. Krähenbühl. Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br. J. Clin. Pharmacol. 45:355–359 (1998).Google Scholar
  6. 6.
    P. Schmiedlin-Ren, D. J. Edwards, M. E. Fitzsimmons, K. He, K. S. Lown, P. M. Woster, A. Rahman, K. E. Thummel, J. M. Fisher, P. F. Hollenberg, and P. B. Watkins. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab. Dispos. 25:1228–1233 (1997).Google Scholar
  7. 7.
    U. Fuhr. Drug interactions with grapefruit juice. Extent, probable mechanisms and clinical relevance. Drug Saf. 18:251–272 (1998).Google Scholar
  8. 8.
    V. J. Wacher, C.-Y. Wu, and L. Z. Benet. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol. Carcinog. 13:129–134 (1995).Google Scholar
  9. 9.
    R. B. Kim, M. F. Fromm, C. Wandel, B. Leake, A. J. J. Wood, D. M. Roden, and G. R. Wilkinson. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J. Clin. Invest. 101:289–294 (1998).Google Scholar
  10. 10.
    J. Van Asperen, O. Van Tellingen, and J. H. Beijnen. The pharmacological role of P-glycoprotein in the intestinal epithelium. Pharmacol. Res. 37:429–435 (1998).Google Scholar
  11. 11.
    L. Z. Benet, C.-Y. Wu, M. F. Hebert, and V. J. Wacher. Intestinal drug metabolism and antitransport processes: A potential paradigm shift in oral drug delivery. J. Contr. Rel. 39:139–143 (1996).Google Scholar
  12. 12.
    V. J. Wacher, L. Salphati, and L. Z. Benet. Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv. Drug Deliv. Rev. 20:99–112 (1996).Google Scholar
  13. 13.
    V. J. Wacher, J. A. Silverman, Y. Zhang, and L. Z. Benet. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J. Pharm. Sci. 87:1322–1330 (1998).Google Scholar
  14. 14.
    H. Takanaga, A. Ohnishi, H. Matsuo, and Y. Sawada. Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in Caco-2 cells. Biol. Pharm. Bull. 21:1062–66 (1998).Google Scholar
  15. 15.
    P. Langguth, S. Neuhoff, C. Regardh, and H. Spahn-Langguth. Grapefruit juice components modify the intestinal permeability of the P-glycoprotein substrate talinolol. Exp. Toxicol. Pathol. 50:117 (1998) (Abstract).Google Scholar
  16. 16.
    L. Z. Benet, T. Izumi, Y. Zhang, J. A. Silverman, and V. J. Wacher. Intestinal MDR transport proteins and P450 enzymes as barriers to oral drug delivery. J. Contr. Rel. In press (1999).Google Scholar
  17. 17.
    I. Pastan, M. M. Gottesman, K. Ueda, E. Lovelace, A. V. Rutherford, and M. C. Willingham. A retrovirus carrying a MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells. Proc. Natl. Acad. Sci. U.S.A. 85:4486–4490 (1988).Google Scholar
  18. 18.
    J. Hunter, M. A. Jepson, T. Tsuruo, N. L. Simmons, and B. H. Hirst. Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells. J. Biol. Chem. 268:14991–14997 (1993).Google Scholar
  19. 19.
    Y. Zhang, and L. Z. Benet. Characterization of P-glycoprotein mediated transport of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor, across MDR1-MDCK and Caco-2 cell monolayers. Pharm. Res. 15:1520–1524 (1998).Google Scholar
  20. 20.
    M. Horio, K.-V. Chin, S. J. Currier, S. Goldenberg, C. Williams, I. Pastan, M. M. Gottesman, and J. Handler. Transepithelial transport of drugs by the multidrug transporter in cultured Madin-Darby canine kidney cell epithelia. J. Biol. Chem. 264:14880–14884 (1989).Google Scholar
  21. 21.
    J. M. Phang, C. M. Poore, J. Lopaczynska, and G. C. Yeh. Flavonol-stimulated efflux of 7,12-dimethylbenz(a)anthracene in multidrug-resistant breast cancer cells. Cancer Res. 53:5977–5981 (1993).Google Scholar
  22. 22.
    J. W. Critchfield, C. J. Welsh, J. M. Phang, and G. C. Yeh. Modulation of adriamycin accumulation and efflux by flavonoids in HCT-15 colon cells. Biochem. Pharmacol. 48:1437–1445 (1994).Google Scholar
  23. 23.
    A. Miniscalco, J. Lundahl, C. G. Regardh, B. Edgar, and U. G. Eriksson. Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice. J. Pharmacol. Exp. Ther. 261:1196–1199 (1992).Google Scholar
  24. 24.
    W. Schubert, U. Eriksson, B. Edgar, G. Cullberg, and T. Hedner. Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17 beta-estradiol. Eur. J. Drug Metab. Pharmacokin. 20:219–224 (1995).Google Scholar
  25. 25.
    A. B. Shapiro and V. Ling. Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur. J. Biochem. 250:130–137 (1997).Google Scholar
  26. 26.
    S. E. Bates, S. J. Currier, M. Alvarez, and A. T. Fojo. Modulation of P-glycoprotein phosphorylation and drug transport by sodium butyrate. Biochemistry 31:6366–6372 (1992).Google Scholar

Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • Andrea Soldner
    • 1
  • Uwe Christians
    • 1
  • Miki Susanto
    • 1
  • Vincent J. Wacher
    • 2
  • Jeffrey A. Silverman
    • 2
  • Leslie Z. Benet
    • 1
  1. 1.Department of Biopharmaceutical Sciences, School of PharmacyUniversity of CaliforniaSan Francisco
  2. 2.AvMax Inc.Berkeley

Personalised recommendations