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Research ArticleArticle

P-Glycoprotein Increases Portal Bioavailability of Loperamide in Mouse by Reducing First-Pass Intestinal Metabolism

Matthew B. Dufek, Beverly M. Knight, Arlene S. Bridges and Dhiren R. Thakker
Drug Metabolism and Disposition March 2013, 41 (3) 642-650; DOI: https://doi.org/10.1124/dmd.112.049965
Matthew B. Dufek
Division of Molecular Pharmaceutics (M.B.D., B.M.K.) and Division of Pharmacotherapy and Experimental Therapeutics (D.R.T.), UNC Eshelman School of Pharmacy; and Department of Pathology and Laboratory Medicine, School of Medicine (A.S.B.), The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Beverly M. Knight
Division of Molecular Pharmaceutics (M.B.D., B.M.K.) and Division of Pharmacotherapy and Experimental Therapeutics (D.R.T.), UNC Eshelman School of Pharmacy; and Department of Pathology and Laboratory Medicine, School of Medicine (A.S.B.), The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Arlene S. Bridges
Division of Molecular Pharmaceutics (M.B.D., B.M.K.) and Division of Pharmacotherapy and Experimental Therapeutics (D.R.T.), UNC Eshelman School of Pharmacy; and Department of Pathology and Laboratory Medicine, School of Medicine (A.S.B.), The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Dhiren R. Thakker
Division of Molecular Pharmaceutics (M.B.D., B.M.K.) and Division of Pharmacotherapy and Experimental Therapeutics (D.R.T.), UNC Eshelman School of Pharmacy; and Department of Pathology and Laboratory Medicine, School of Medicine (A.S.B.), The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Abstract

P-glycoprotein (P-gp) and CYP3A (cytochrome P450 3A, generally; Cyp3a, rodent enzyme) in the intestine can attenuate absorption of orally administered drugs. While some suggest that P-gp enhances intestinal metabolism by CYP3A/Cyp3a during absorption of a dual substrate, others suggest that P-gp reduces the metabolism in the intestine when substrates are at subsaturating concentrations. Hence, to elucidate the cellular mechanisms that can address these divergent reports, we studied intestinal absorption of the dual substrate loperamide in portal vein-cannulated P-gp–competent and P-gp–deficient mice. These studies showed that at low doses of loperamide, which produced intestinal concentrations near the apparent Km for oxidative metabolism, the bioavailability across the intestine (FG) was 6-fold greater in the P-gp–competent mice than in P-gp–deficient mice. The higher FG of loperamide in the presence of P-gp was attributed to lower loperamide intestinal metabolism. However, at high doses of loperamide, the sparing of first-pass metabolism by P-gp was balanced against the attenuation of absorption by apical efflux, resulting in no net effect on FG. In vitro studies with intestinal tissue from P-gp–competent and -deficient mice confirmed that P-gp reduced the metabolic rate of loperamide during absorptive flux at concentrations near Km but had little effect on metabolism at higher (saturating) concentrations. Further, studies in which Cyp3a was chemically inactivated by aminobenzotriazole in P-gp–competent and -deficient mice, showed that P-gp and Cyp3a individually attenuated FG by 8-fold and 70-fold, respectively. These results confirmed that P-gp effectively protects loperamide at low doses from intestinal first-pass metabolism during intestinal absorption.

Footnotes

  • Financial support for this research was provided by a research grant from Pfizer Inc.

  • dx.doi.org/10.1124/dmd.112.049965.

  • Received November 5, 2012.
  • Accepted January 3, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (3)
Drug Metabolism and Disposition
Vol. 41, Issue 3
1 Mar 2013
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Research ArticleArticle

Enhancement of the Bioavailability of Loperamide by P-gp

Matthew B. Dufek, Beverly M. Knight, Arlene S. Bridges and Dhiren R. Thakker
Drug Metabolism and Disposition March 1, 2013, 41 (3) 642-650; DOI: https://doi.org/10.1124/dmd.112.049965

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Research ArticleArticle

Enhancement of the Bioavailability of Loperamide by P-gp

Matthew B. Dufek, Beverly M. Knight, Arlene S. Bridges and Dhiren R. Thakker
Drug Metabolism and Disposition March 1, 2013, 41 (3) 642-650; DOI: https://doi.org/10.1124/dmd.112.049965
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