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Research ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

In Vitro P-glycoprotein Efflux Ratio Can Predict the In Vivo Brain Penetration Regardless of Biopharmaceutics Drug Disposition Classification System Class

Ryota Kikuchi, Sonia M. de Morais and J. Cory Kalvass
Drug Metabolism and Disposition December 2013, 41 (12) 2012-2017; DOI: https://doi.org/10.1124/dmd.113.053868
Ryota Kikuchi
Drug Metabolism, Pharmacokinetics, and Bioanalysis, AbbVie Inc., North Chicago, Illinois
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Sonia M. de Morais
Drug Metabolism, Pharmacokinetics, and Bioanalysis, AbbVie Inc., North Chicago, Illinois
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J. Cory Kalvass
Drug Metabolism, Pharmacokinetics, and Bioanalysis, AbbVie Inc., North Chicago, Illinois
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Abstract

P-glycoprotein (P-gp) is expressed at the blood-brain barrier (BBB) and restricts the penetration of its substrates into the central nervous system (CNS). In vitro substrate assessment for P-gp is frequently used to predict the in vivo relevance of P-gp-mediated efflux at the BBB. We have conducted a comprehensive review of literature focusing on the in vitro–in vivo correlation of P-gp efflux ratio (ER), and demonstrated that in vitro substrates of P-gp are also in vivo substrates at the BBB. It was of note that the in vitro ER in the MDCK-MDR1 cell line from National Institutes of Health was found to be a better predictor of in vivo ER than that from Netherlands Cancer Institute, with r2 values of 0.813 and 0.531, respectively. Recently, a research group proposed that 98% of Biopharmaceutics Drug Disposition Classification System (BDDCS) class 1 drugs can penetrate the brain even when those compounds are shown as P-gp substrates in vitro. However, our data analysis suggested that in vitro ER can predict the in vivo brain penetration regardless of the class in BDDCS. Considering that very few marketed CNS drugs are in vivo substrates for P-gp, the in vitro substrate assessment of P-gp should be used in the early stages of drug discovery to select compounds that are most likely to penetrate the CNS to exert their pharmacologic action.

Footnotes

    • Received July 23, 2013.
    • Accepted September 4, 2013.
  • Ryota Kikuchi, J. Cory Kalvass, and Sonia M. de Morais are employees of AbbVie. The presentation contains no proprietary AbbVie data.

  • dx.doi.org/10.1124/dmd.113.053868.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (12)
Drug Metabolism and Disposition
Vol. 41, Issue 12
1 Dec 2013
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Research ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

In Vitro–In Vivo Correlation of P-gp Efflux Ratio

Ryota Kikuchi, Sonia M. de Morais and J. Cory Kalvass
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2012-2017; DOI: https://doi.org/10.1124/dmd.113.053868

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Research ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

In Vitro–In Vivo Correlation of P-gp Efflux Ratio

Ryota Kikuchi, Sonia M. de Morais and J. Cory Kalvass
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2012-2017; DOI: https://doi.org/10.1124/dmd.113.053868
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