Abstract
Purpose. The aim of this study is to investigate the effects of 50% ethyl acetate extracts of grapefruit juice (GFJ) and orange juice (OJ) on the transport activity of P-glycoprotein (P-gp) in the rat small intestine.
Methods.The efflux of P-gp substrates from rat everted sac in the absence or presence of verapamil, GFJ, OJ or erythromycin was measured. Rhodamine123, fexofenadine and saquinavir were used as P-gp substrates. P-gp expression levels in the rat jejunum and ileum were determined by Western blot analysis.
Results. The efflux of rhodamine123 from the everted sac increased from the apex of the jejunum to the low ileum and the expression of P-gp in the ileum was 2.31-fold higher than that in the jejunum. Verapamil and the 50% GFJ and OJ extracts inhibited the efflux from the intestine of all three drugs tested. Erythromycin decreased the efflux of rhodamine123 and fexofenadine, but did not affect the efflux of saquinavir in the intestine.
Conclusions. GFJ and OJ extracts inhibited the efflux of P-gp substrates from the small intestine. Therefore, they may enhance the oral bioavailability of P-gp substrates by increasing absorption in the small intestine.
Similar content being viewed by others
REFERENCES
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).
K. Hashimoto, T. Shirafuji, H. Sekino, O. Matsuoka, H. Sekino, O. Onnagawa, T. Okamoto, S. Kudo, and J. Azuma. Interaction of citrus juices with pranidipine, a new 1, 4-dihydropyridine calcium antagonist, in healthy subjects. Eur. J. Clin. Pharmacol. 54:753–760 (1998).
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).
H. H. T. Kupferschmidt, K. E. Fattinger, H. R. Ha, F. Follath, and S. Krahenbuhl. Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br. J. Clin. Pharmacol. 45:355–359 (1998).
Y. M. Ku. D. I. Min, and M. Flanigan. Effect of grapefruit juice on the pharmacokinetics of microemulsion cyclosporine and its metabolite in healthy volunteers: does the formulation difference matter? J. Clin. Pharmacol. 38:959–965 (1998).
H. H. T. Kupferschmidt, H. R. Ha, W. H. Ziegler, P. J. Meier, and S. Krahenbuhl. Interaction between grapefruit juice and midazolam in humans. Clin. Pharmacol. Ther. 58:20–28 (1995).
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).
D. G. Bailey, J. D. Spence, C. Munoz, and J. M. Arnold. Interaction of citrus juices with felodipine and nifedipine. Lancet 337:268–269 (1991).
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. 21:1062–1066 (1998).
A. Ohnishi, H. Matsuo, S. Yamada, H. Takanaga, S. Morimoto, Y. Shoyama, H. Ohtani, and Y. Sawada. Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4. Br. J. Pharmacol. 130:1369–1377 (2000).
H. Takanaga, A. Ohnishi, S. Yamada, H. Matsuo, S. Morimoto, Y. Shoyama, H. Ohtani, and Y. Sawada. Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4. J. Pharmacol. Exp. Ther. 293:230–236 (2000).
T. Terao, E. Hisanaga, Y. Sai, I. Tamai, and A. Tsuji. Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier. J. Pharm. Pharmacol. 48:1083–1089 (1996).
C. Lippert, J. Ling, P. Brown, S. Burmaster, M. Eller, L. Cheng, R. Thompson, and S. Weir. Mass balance and pharmacokinetics of MDL 16,455A in healthy, male volunteers. Pharm. Res. 12:S390 (1995).
M. Cvetkovic, B. Leake, M. F. Fromm, G. R. Wilkinson, and R. B. Kim. Oatp and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab. Dispos. 27:866–871 (1999).
V. D. Makhey and P. J. Sinko. Investigation of stability, cytochrome P450-mediated metabolism and MDR-mediated efflux of the HIV protease inhibitor, saquinavir in humans and rats. Pharm. Res. 14:S525–S526 (1997).
L. Jette, E. Beaulieu, J. Leclerc, and R. Beliveau. Cyclosporin A treatment induces overexpression of P-glycoprotein in the kidney and other tissues. Am. Physiol. Sci. 270:F756–F765 (1996).
O. H. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randall. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–275 (1951).
U. K. Laemmli. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685 (1970).
R. Yumoto, T. Murakami, Y. Nakamoto, R. Hasegawa, J. Nagai, and M. Takano. Transport of rhodamine 123, a P-glycoprotein substrate, across rat intestine and Caco-2 cell monolayers in the presence of cytochrome P-450 3A-related compounds. J. Pharmacol. Exp. Ther. 289:149–155 (1999).
J. Chianale, V. Vollrath, A. M. Wielandt, S. Miranda, R. Gonzalez, A. M. Fresno, C. Quintana, S. Gonzalez, L. Andrade, and S. Guzman. Differences between nuclear run-off and mRNA levels for multidrug resistance gene expression in the cephalocaudal axis of the mouse intestine. Biochim. Biophys. Acta 1264:369–376 (1995).
V. D. Makhey, A. Guo, D. A. Norris, P. Hu, J. Yan, and P. J. Sinko. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells. Pharm. Res. 15:1160–1167 (1998).
A. E. O. Trezise, P. R. Romano, D. R. Gill, S. C. Hyde, F. V. Sepulveda, M. Buchwald, and C. F. Higgins. The multidrug resistance and cystic fibrosis genes have complementary patterns of epithelial expression. EMBO J. 11:4291–4303 (1992).
T. Ikegawa, F. Ushigome, N. Koyabu, S. Morimoto, Y. Shoyama, M. Naito, T. Tsuruo, H. Ohtani, and Y. Sawada. Inhibition of P-glycoprotein by orange juice components, polymethoxyflavones in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. Cancer Lett. 160:21–28 (2000).
A. Soldner, U. Christians, M. Susanto, V. J. Wacher, J. A. Silverman, and L. Z. Benet. Grapefruit juice activates P-glycoprotein-mediated drug transport. Pharm. Res. 16:478–485 (1999).
B. Edgar, C. G. Regardh, G. Johnsson, L. Johansson, P. Lundborg, I. Lofberg, and O. Ronn. Felodipine kinetics in healthy men. Clin. Pharmacol. Ther. 38:205–211 (1985).
D. J. Edwards, M. E. Fitzsimmons, E. G. Schuetz, K. Yasuda, M. P. Ducharme, L. H. Warbasse, P. M. Woster, J. D. Schuetz, and P. Watkins. 6', 7'-Dihydroxybergamottin in grapefruit juice and seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin. Pharmacol. Ther. 65:237–244 (1999).
T. Russell, M. Stoltz, and S. Weir. Pharmacokinetics, pharmacodynamics, and tolerance of single-and multiple-dose fexofenadine hydrochloride in healthy male volunteers. Clin. Pharmacol. Ther. 64:612–621 (1998).
C. M. Pratt, J. Mason, T. Russell, R. Reynolds, and R. Ahlbrandt. Cardiovascular safety of fexofenadine HCl. Am. J. Cardiol. 83:1451–1454 (1999).
V. A. Eagling, L. Profit, and D. J. Back. Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease ihhibitor saquinavir by grapefruit juie components. Br. J. Clin. Pharmacol. 48:543–552 (1999).
M. Takano, R. Hasegawa, T. Fukuda, R. Yumoto, J. Nagai, and T. Murakami. Interaction with P-glycoprotein and transport of erythromycin, midazolam and ketoconazole in Caco-2 cells. Eur. J. Pharmacol. 358:289–294 (1998).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tian, R., Koyabu, N., Takanaga, H. et al. Effects of Grapefruit Juice and Orange Juice on the Intestinal Efflux of P-Glycoprotein Substrates. Pharm Res 19, 802–809 (2002). https://doi.org/10.1023/A:1016100715125
Issue Date:
DOI: https://doi.org/10.1023/A:1016100715125