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Research ArticleArticle

Coadministration of P-Glycoprotein Modulators on Loperamide Pharmacokinetics and Brain Distribution

Rita Nieto Montesinos, Brice Moulari, Jessica Gromand, Arnaud Beduneau, Alf Lamprecht and Yann Pellequer
Drug Metabolism and Disposition April 2014, 42 (4) 700-706; DOI: https://doi.org/10.1124/dmd.113.055566
Rita Nieto Montesinos
Laboratory of Pharmaceutical Engineering, University of Franche-Comté, Besançon, France
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Brice Moulari
Laboratory of Pharmaceutical Engineering, University of Franche-Comté, Besançon, France
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Jessica Gromand
Laboratory of Pharmaceutical Engineering, University of Franche-Comté, Besançon, France
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Arnaud Beduneau
Laboratory of Pharmaceutical Engineering, University of Franche-Comté, Besançon, France
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Alf Lamprecht
Laboratory of Pharmaceutical Engineering, University of Franche-Comté, Besançon, France
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Yann Pellequer
Laboratory of Pharmaceutical Engineering, University of Franche-Comté, Besançon, France
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Abstract

The efflux transporter P-glycoprotein, expressed at high levels at the blood-brain barrier, exerts a profound effect on the disposition of various therapeutic compounds in the brain. A rapid and efficient modulation of this efflux transporter could enhance the distribution of its substrates and thereby improve central nervous system pharmacotherapies. This study explored the impact of the intravenous coadministration of two P-glycoprotein modulators, tariquidar and elacridar, on the pharmacokinetics and brain distribution of loperamide, a P-glycoprotein substrate probe, in rats. After 1 hour postdosing, tariquidar and elacridar, both at a dose of 1.0 mg/kg, increased loperamide levels in the brain by 2.3- and 3.5-fold, respectively. However, the concurrent administration of both P-glycoprotein modulators, each at a dose of 0.5 mg/kg, increased loperamide levels in the brain by 5.8-fold and resulted in the most pronounced opioid-induced clinical signs. This phenomenon may be the result of a combined noncompetitive modulation by tariquidar and elacridar. Besides, the simultaneous administration of elacridar and tariquidar did not significantly modify the pharmacokinetic parameters of loperamide. This observation potentially allows the concurrent use of low but therapeutic doses of P-gp modulators to achieve full inhibitory effects.

Footnotes

    • Received October 25, 2013.
    • Accepted January 7, 2013.
  • This work was partially supported by a French Government grant managed by the French National Research Agency under the program “Investissements d’Avenir” [ANR-11-LABX-0021]. R.N.M. gratefully acknowledges the region of Franche-Comté for financial support [Grant 2009C-07455].

  • dx.doi.org/10.1124/dmd.113.055566.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleArticle

Coadministration of Elacridar and Tariquidar

Rita Nieto Montesinos, Brice Moulari, Jessica Gromand, Arnaud Beduneau, Alf Lamprecht and Yann Pellequer
Drug Metabolism and Disposition April 1, 2014, 42 (4) 700-706; DOI: https://doi.org/10.1124/dmd.113.055566

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Research ArticleArticle

Coadministration of Elacridar and Tariquidar

Rita Nieto Montesinos, Brice Moulari, Jessica Gromand, Arnaud Beduneau, Alf Lamprecht and Yann Pellequer
Drug Metabolism and Disposition April 1, 2014, 42 (4) 700-706; DOI: https://doi.org/10.1124/dmd.113.055566
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