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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Species Difference in the Effect of Grapefruit Juice on Intestinal Absorption of Talinolol between Human and Rat

Yoshiyuki Shirasaka, Erika Kuraoka, Hildegard Spahn-Langguth, Takeo Nakanishi, Peter Langguth and Ikumi Tamai
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 181-189; DOI: https://doi.org/10.1124/jpet.109.159756
Yoshiyuki Shirasaka
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Erika Kuraoka
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Hildegard Spahn-Langguth
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Takeo Nakanishi
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Peter Langguth
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Ikumi Tamai
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Abstract

Bioavailability of talinolol, a β1-adrenergic receptor antagonist, was enhanced by coadministration with grapefruit juice (GFJ) in rats, whereas GFJ ingestion markedly reduced the absorption of talinolol in humans. Because our recent study indicated that the inhibitory effect of GFJ on organic anion-transporting polypeptide (Oatp)- and P-gp-mediated talinolol absorption depends on the concentration of naringin in ingested GFJ, the apparent inconsistent findings may be explained by the species difference in the affinity of naringin for OATP/Oatp and P-gp multidrug resistance 1 (MDR1/Mdr1) between humans and rats. Although human MDR1-mediated talinolol transport was not inhibited by 2000 μM naringin, naringin inhibited human OATP1A2-, rat Oatp1a5-, and rat Mdr1a-mediated talinolol transport with IC50 values of 343, 12.7, and 604 μM, respectively, in LLC-PK1 cell and Xenopus laevis oocyte systems. Because the naringin concentration in commercially prepared GFJ was found to be approximately 1200 μM, these results suggested that GFJ would reduce the intestinal absorption of talinolol through inhibition of OATP1A2-mediated talinolol uptake in humans, whereas an increase of talinolol absorption is mainly through inhibition of Mdr1a-mediated efflux in rats. The rat intestinal permeability of talinolol measured by the in situ closed loop method was indeed significantly increased in the presence of GFJ, whereas a significant decrease was observed with 6-fold diluted GFJ, in which the naringin concentration was approximately 200 μM. The present study indicated that the species difference in the effect of GFJ on intestinal absorption of talinolol between humans and rats may be due to differences in the affinity of naringin for OATP/Oatp and MDR1/Mdr1 transporters between the two species.

Footnotes

  • This work was supported in part by a Grant-in-aid for Scientific Research from Japan Society for the Promotion of Science [Research Project Number 21790147].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.159756

  • ABBREVIATIONS:

    P-gp
    P-glycoprotein
    AUC
    area under the plasma concentration-time curve
    AP
    apical
    BL
    basolateral
    GI
    gastrointestinal
    GFJ
    grapefruit juice
    MDR/Mdr
    multidrug resistance
    OATP/Oatp
    organic anion-transporting polypeptide
    Papp
    apparent permeability
    SLC
    solute carrier
    TEER
    transepithelial electrical resistance
    LC/MS
    liquid chromatography/mass spectrometry.

    • Received August 4, 2009.
    • Accepted September 21, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Species Difference in the Effect of Grapefruit Juice on Intestinal Absorption of Talinolol between Human and Rat

Yoshiyuki Shirasaka, Erika Kuraoka, Hildegard Spahn-Langguth, Takeo Nakanishi, Peter Langguth and Ikumi Tamai
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 181-189; DOI: https://doi.org/10.1124/jpet.109.159756

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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Species Difference in the Effect of Grapefruit Juice on Intestinal Absorption of Talinolol between Human and Rat

Yoshiyuki Shirasaka, Erika Kuraoka, Hildegard Spahn-Langguth, Takeo Nakanishi, Peter Langguth and Ikumi Tamai
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 181-189; DOI: https://doi.org/10.1124/jpet.109.159756
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