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Research ArticleArticle

Use of the Øie-Tozer Model in Understanding Mechanisms and Determinants of Drug Distribution

Nigel J. Waters and Franco Lombardo
Drug Metabolism and Disposition July 2010, 38 (7) 1159-1165; DOI: https://doi.org/10.1124/dmd.110.032458
Nigel J. Waters
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Franco Lombardo
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Abstract

Volume of distribution (VD) is a key pharmacokinetic property that together with clearance determines the half-life or residence time of drug in the body. It is commonly expressed as steady-state volume of distribution VDss with a physiological basis for its understanding developed by Øie and Tozer in 1979. The Øie-Tozer equation uses terms for plasma protein binding (fup), tissue binding (fut), and the extravascular/intravascular ratio of albumin as well as constants for the volumes of plasma, extracellular fluid, and tissue. We explored this model using a data set of 553 drugs for which VDss and plasma protein binding were available in humans. Eighteen percent of cases (102 compounds) did not obey the Øie-Tozer model, with the rearranged equation giving an aberrant fut value (fut < 0 or fut > 1), in particular for compounds with VDss < 0.6 l/kg and fup > 0.1. Further analysis of this group of compounds revealed patterns in physicochemical attributes with a high proportion exemplified by logP less than 0 (i.e., very hydrophilic), polar surface area >150 Å2, and a difference between logP and logD >2.5. In addition there was a high representation of certain drug classes including anti-infectives as well as neuromuscular blockers and contrast agents. The majority of compounds were also found to have literature evidence, implicating active transport processes in their disposition. This analysis provides some important insights for pharmacokinetic optimization in this particular chemical space, as well as in the application of the Øie-Tozer model for predicting volume of distribution in humans.

Footnotes

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

    doi:10.1124/dmd.110.032458.

  • ABBREVIATIONS:

    VD
    volume of distribution
    VDss
    volume of distribution at steady-state
    Mdr/mdr
    multidrug resistance protein
    fut
    fraction unbound in tissue
    fup
    fraction unbound in plasma
    RE/I
    extravascular-to-intravascular binding protein ratio
    PSA
    polar surface area.

  • Received January 27, 2010.
  • Accepted April 7, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Research ArticleArticle

Use of the Øie-Tozer Model in Understanding Mechanisms and Determinants of Drug Distribution

Nigel J. Waters and Franco Lombardo
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1159-1165; DOI: https://doi.org/10.1124/dmd.110.032458

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Research ArticleArticle

Use of the Øie-Tozer Model in Understanding Mechanisms and Determinants of Drug Distribution

Nigel J. Waters and Franco Lombardo
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1159-1165; DOI: https://doi.org/10.1124/dmd.110.032458
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