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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Modulation of P-glycoprotein Transport Activity in the Mouse Blood-Brain Barrier by Rifampin

Jian Zong and Gary M. Pollack
Journal of Pharmacology and Experimental Therapeutics August 2003, 306 (2) 556-562; DOI: https://doi.org/10.1124/jpet.103.049452
Jian Zong
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Gary M. Pollack
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Abstract

The objective of the present study was to examine the time course and concentration dependence of modulation of P-glycoprotein (P-gp) activity in the blood-brain barrier (BBB) with consequent influence on substrate uptake into brain tissue. Potential P-gp inducers (rifampin and morphine) were administered subchorionically to P-gp-competent [mdr1a(+/+)] mice to induce P-gp expression in brain; the impact of rifampin pretreatment on brain penetration of verapamil also was evaluated with an in situ brain perfusion technique. In addition, the effect of single-dose rifampin on P-gp BBB transport activity was assessed with brain perfusion using verapamil and quinidine as model P-gp substrates. Chronic exposure to rifampin or morphine induced P-gp expression in mouse brain to a modest extent. However, single-dose rifampin treatment increased the brain uptake of verapamil and quinidine in mdr1a(+/+) mice in a dose- and concentration-dependent manner, consistent with P-gp inhibition. Maximum inhibition of P-gp-mediated efflux of verapamil by rifampin pretreatment in vivo (150 mg/kg) was ∼55%, whereas there was only ∼12% inhibition of P-gp-mediated efflux of quinidine at that rifampin dose. Coperfusion of rifampin at a concentration of 500 μM abolished P-gp-mediated efflux of verapamil at the BBB. However, only ∼40% inhibition of P-gp-mediated efflux of quinidine was observed with coperfusion of rifampin, even at a 2-fold higher rifampin concentration (1000 μM). The present studies demonstrate that P-gp function at the BBB can be modulated by rifampin in a dose- and concentration-dependent manner. The degree to which rifampin inhibits P-gp-mediated transport is dependent on the substrate molecule.

Footnotes

  • This project was supported in part by National Institutes of Health Grant GM61191.

  • DOI: 10.1124/jpet.103.049452.

  • ABBREVIATIONS: P-gp, P-glycoprotein; MDR, multidrug resistance; BBB, blood-brain barrier; DMSO, dimethyl sulfoxide; CLup, uptake clearance; HPLC, high-performance liquid chromatography; PSC833, valspodar; H33342, 2-(4-ethoxyphenyl)-5-(4-methyl-1-piperazinyl)-2,5-bi-1H-benzimidazole trihydrochloride.

    • Received January 22, 2003.
    • Accepted April 3, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 2
1 Aug 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Modulation of P-glycoprotein Transport Activity in the Mouse Blood-Brain Barrier by Rifampin

Jian Zong and Gary M. Pollack
Journal of Pharmacology and Experimental Therapeutics August 1, 2003, 306 (2) 556-562; DOI: https://doi.org/10.1124/jpet.103.049452

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Modulation of P-glycoprotein Transport Activity in the Mouse Blood-Brain Barrier by Rifampin

Jian Zong and Gary M. Pollack
Journal of Pharmacology and Experimental Therapeutics August 1, 2003, 306 (2) 556-562; DOI: https://doi.org/10.1124/jpet.103.049452
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