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Research ArticleArticle

Scaling of in Vitro Membrane Permeability to Predict P-glycoprotein-Mediated Drug Absorption in Vivo

Yoshiyuki Shirasaka, Yoshie Masaoka, Makoto Kataoka, Shinji Sakuma and Shinji Yamashita
Drug Metabolism and Disposition May 2008, 36 (5) 916-922; DOI: https://doi.org/10.1124/dmd.107.020040
Yoshiyuki Shirasaka
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Yoshie Masaoka
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Makoto Kataoka
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Shinji Sakuma
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Shinji Yamashita
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Abstract

In a previous study, the concentration-dependent permeability of P-glycoprotein (P-gp) substrate drugs, quinidine, verapamil, and vinblastine, in several cell monolayers with different levels of P-gp expression was analyzed kinetically to obtain fundamental parameters for P-gp-mediated transport, Vmax and Km(app) values. Both Vmax and Km(app) values of each drug were found to show linear correlations with the expression level of P-gp. These findings imply the possibility of estimating the Vmax and Km(app) values of P-gp substrate drugs in the in vivo intestinal membrane on the basis of the P-gp expression level. In the present study, concentration-dependent drug permeability to the rat small intestines (upper jejunum and ileum) was simulated on the basis of Vmax and Km(app) values of each drug estimated from the P-gp expression level in the rat small intestines. To validate the predictability of these procedures, drug permeability in the rat small intestines was measured by the in situ single-pass perfusion method. It was confirmed that simulated permeability of each drug in the rat jejunum and ileum corresponded well with permeability measured by the in situ single-pass perfusion method. This study clearly demonstrated the potential to estimate the permeability of P-gp substrate drugs in the human intestine from its P-gp expression level and thus the possibility to predict the oral absorption of those drugs.

Footnotes

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

  • doi:10.1124/dmd.107.020040.

  • ABBREVIATIONS: P-gp, P-glycoprotein; ABC, ATP-binding cassette; MDR/mdr, multidrug resistance; AP, apical; BL, basal; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

    • Received December 6, 2007.
    • Accepted February 13, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (5)
Drug Metabolism and Disposition
Vol. 36, Issue 5
1 May 2008
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Research ArticleArticle

Scaling of in Vitro Membrane Permeability to Predict P-glycoprotein-Mediated Drug Absorption in Vivo

Yoshiyuki Shirasaka, Yoshie Masaoka, Makoto Kataoka, Shinji Sakuma and Shinji Yamashita
Drug Metabolism and Disposition May 1, 2008, 36 (5) 916-922; DOI: https://doi.org/10.1124/dmd.107.020040

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Research ArticleArticle

Scaling of in Vitro Membrane Permeability to Predict P-glycoprotein-Mediated Drug Absorption in Vivo

Yoshiyuki Shirasaka, Yoshie Masaoka, Makoto Kataoka, Shinji Sakuma and Shinji Yamashita
Drug Metabolism and Disposition May 1, 2008, 36 (5) 916-922; DOI: https://doi.org/10.1124/dmd.107.020040
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