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Research ArticleArticle

Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice

Christoffer Bundgaard, Christian Jes Nyberg Jensen and Mats Garmer
Drug Metabolism and Disposition March 2012, 40 (3) 461-466; DOI: https://doi.org/10.1124/dmd.111.043083
Christoffer Bundgaard
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Christian Jes Nyberg Jensen
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Mats Garmer
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Abstract

The experiments described herein compared the extent of in vivo P-glycoprotein (P-gp)-mediated brain efflux between rats and mice for a set of known central nervous system compounds. With use of newly introduced genetically modified mdr1a-deficient rats and their gene-competent counterparts, the brain to plasma distribution was assessed and compared with the distribution pattern in mdr1a-deficient and wild-type mice. Four compounds (aripiprazole, citalopram, risperidone, and venlafaxine) were administered using a continuous subcutaneous osmotic minipump infusion paradigm. Steady-state brain and plasma concentrations of the compounds, including selected metabolites (9-hydroxyrisperidone, O-desmethyl-venlafaxine and N-desmethyl-venlafaxine) were measured in mdr1a-deficient rats and mice and their wild-type counterparts along with their free fractions to determine total and unbound brain to plasma distribution between genotypes within and between species. The results revealed qualitative as well as quantitative similarities between P-gp functionality in vivo at the blood-brain barrier level in rats and mice. All compounds tested were shown to have a significantly higher brain to plasma distribution in both mdr1a-deficient rats and mice compared with that in their wild-type counterparts. Moreover, the relative enhancement in extent of brain penetration between mdr1a-deficient and wild-type rats could be directly correlated to the enhancement ratios obtained in mice. From the unbound brain to unbound plasma distributions, the impact of P-gp on the overall brain penetration capabilities showed minor differences between rats and mice for the compounds tested. In conclusion, a comparable functional role of P-gp between rats and mice with respect to brain efflux mediated by this transporter is suggested.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.043083.

  • ABBREVIATIONS:

    BBB
    blood-brain barrier
    CNS
    central nervous system
    P-gp
    P-glycoprotein
    ABC
    ATP-binding cassette
    MDR/mdr
    multidrug resistance.

  • Received September 30, 2011.
  • Accepted November 23, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

BRAIN EFFLUX COMPARISON BETWEEN P-gp KNOCKOUT RATS AND MICE

Christoffer Bundgaard, Christian Jes Nyberg Jensen and Mats Garmer
Drug Metabolism and Disposition March 1, 2012, 40 (3) 461-466; DOI: https://doi.org/10.1124/dmd.111.043083

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Research ArticleArticle

BRAIN EFFLUX COMPARISON BETWEEN P-gp KNOCKOUT RATS AND MICE

Christoffer Bundgaard, Christian Jes Nyberg Jensen and Mats Garmer
Drug Metabolism and Disposition March 1, 2012, 40 (3) 461-466; DOI: https://doi.org/10.1124/dmd.111.043083
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