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Research ArticleArticle

The Impact of Hepatic Uptake on the Pharmacokinetics of Organic Anions

Philip Gardiner and Stuart W. Paine
Drug Metabolism and Disposition October 2011, 39 (10) 1930-1938; DOI: https://doi.org/10.1124/dmd.111.039842
Philip Gardiner
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Stuart W. Paine
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Abstract

The disposition of seven marketed and two AstraZeneca acid (organic anion) compounds with a range of volume of distribution at steady state (Vss) and clearance have been profiled in rat and dog. Pharmacokinetic (PK) parameters along with liver and muscle tissue levels were collected, and their contributions to total Vss were calculated. The physiologically based prediction of Vss correlated (all predictions within 2-fold) with the Vss obtained from plasma PK analysis. The Vss of the acid drugs with atypically high values could be explained by significant sequestering of compound to the liver. A “media loss” in the in vitro hepatocyte assay that monitors loss of compound from the incubation media along with physiologically based PK (PBPK) modeling was assessed for its ability to accurately predict the impact of hepatic uptake on both clearance and Vss. This methodology significantly improved the prediction of metabolic in vivo clearance compared with standard hepatocyte scaling approaches that do not take into account hepatic uptake. Predictions of Vss from the media loss assay also correlate with the measured values from plasma PK analysis. However, hepatic uptake will have little overall impact on half-life, because of the concomitant impact on both Cl and Vss, as long as hepatic extraction is not high. The methodology described here is particularly useful when there is no allometric relationship between species as a result of interspecies differences in liver uptake. In this situation, the potential use of human hepatocytes combined with PBPK modeling avoids the question of which species pharmacokinetics is most predictive to humans.

Footnotes

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

    doi:10.1124/dmd.111.039842.

  • ABBREVIATIONS:

    PK
    pharmacokinetic(s)
    CL
    clearance
    Vd
    volume of distribution
    Vss
    volume of distribution at steady state
    PBPK
    physiologically based pharmacokinetics
    CLinc
    clearance from the incubation
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    CLmed
    clearance from the medium
    kmem
    proportionality constant between amount in membrane and concentration in medium
    CLint, met
    unbound metabolic intrinsic clearance
    fmed, ss
    fraction in the medium at steady state
    fuinc
    fraction unbound in the incubation
    CLint, L, pass
    liver unbound passive diffusion intrinsic clearance
    CLint, L, uptake
    liver unbound sinusoidal uptake intrinsic clearance
    CLint, L, efflux
    liver unbound sinusoidal efflux intrinsic clearance
    CLint, L
    liver unbound intrinsic clearance
    CLint, pass
    unbound passive diffusion intrinsic clearance
    CLint, efflux
    unbound sinusoidal efflux intrinsic clearance
    CLint, uptake
    unbound sinusoidal uptake intrinsic clearance
    kL, mem
    proportionality constant between free blood concentration and the amount of drug in the cell membranes of the liver.

  • Received March 31, 2011.
  • Accepted July 21, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
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Research ArticleArticle

IMPACT OF HEPATIC UPTAKE ON PK OF ORGANIC ANIONS

Philip Gardiner and Stuart W. Paine
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1930-1938; DOI: https://doi.org/10.1124/dmd.111.039842

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Research ArticleArticle

IMPACT OF HEPATIC UPTAKE ON PK OF ORGANIC ANIONS

Philip Gardiner and Stuart W. Paine
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1930-1938; DOI: https://doi.org/10.1124/dmd.111.039842
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