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Research ArticleArticle

Prediction of the Pharmacokinetics of Atorvastatin, Cerivastatin, and Indomethacin Using Kinetic Models Applied to Isolated Rat Hepatocytes

Stuart W. Paine, Alison J. Parker, Philip Gardiner, Peter J. H. Webborn and Robert J. Riley
Drug Metabolism and Disposition July 2008, 36 (7) 1365-1374; DOI: https://doi.org/10.1124/dmd.107.019455
Stuart W. Paine
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Alison J. Parker
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Philip Gardiner
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Peter J. H. Webborn
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Robert J. Riley
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Abstract

The disposition of atorvastatin, cerivastatin, and indomethacin, established substrates of rat hepatic basolateral uptake transporters, has been evaluated in suspended rat hepatocytes. Cell and media concentration-time data were simultaneously fitted to a model incorporating active uptake, permeation, binding, and metabolism. Use of the model to estimate the ratio of intracellular to extracellular steady-state free drug concentrations demonstrated the strong influence of active uptake on the kinetics of atorvastatin (18:1) and cerivastatin (8:1), in comparison with indomethacin (3.5:1). Indomethacin, however, was shown to have a higher uptake clearance (599 ± 101 μl/min/106 cells) than atorvastatin (375 ± 45 μl/min/106 cells) and cerivastatin (413 ± 47 μl/min/106 cells). The high passive permeability of indomethacin (237 ± 63 μl/min/106 cells) clearly negated the effect of the active transport on the overall disposition. An analogous physiological model was constructed that allowed prediction of the in vivo pharmacokinetics, including the free intracellular concentration in liver. Hepatic clearance was well predicted by the model, in contrast to predictions based on standard methods. Volume of distribution was well predicted for indomethacin and predicted reasonably for atorvastatin and cerivastatin and higher than might be expected for an acid compound. Furthermore, the terminal half-life predictions for all three compounds were within 2-fold of the observed values. The ability to estimate the free-intracellular hepatic concentration of uptake substrates has major benefits in terms of predicting pharmacokinetics, potential CYP-mediated drug-drug interactions, and efficacy of hepatically targeted therapeutics.

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

  • doi:10.1124/dmd.107.019455.

  • ABBREVIATIONS: CLint,met, unbound metabolic intrinsic clearance; CLinc, clearance from the incubation; CLint,L, liver unbound intrinsic clearance; fuinc, fraction unbound in the incubation; DMSO, dimethyl sulfoxide; LC-MS/MS, liquid chromatography/tandem mass spectrometry; CLint,efflux, unbound sinusoidal efflux intrinsic clearance; CLint,uptake, unbound sinusoidal uptake intrinsic clearance; CLint,pass, unbound passive diffusion intrinsic clearance; kmem, proportionality constant between amount in membrane and concentration in medium; fmed,60, fraction in the medium at 60 min; Vss, steady-state volume of distribution; CLmed, clearance from the medium; fucell, unbound fraction of drug within the cells; fmed,ss, fraction in the medium at steady-state; T, tissue; I, interstitial fluid; LV, liver vascular; L,mem, liver cell membrane; LI, liver interstitial; L,cell, liver cellular; 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; kL,mem, proportionality constant between free blood concentration and the amount of drug in the cell membranes of the liver; MRT, mean residence time.

  • ↵ Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received October 29, 2007.
    • Accepted April 17, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (7)
Drug Metabolism and Disposition
Vol. 36, Issue 7
1 Jul 2008
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Research ArticleArticle

Prediction of the Pharmacokinetics of Atorvastatin, Cerivastatin, and Indomethacin Using Kinetic Models Applied to Isolated Rat Hepatocytes

Stuart W. Paine, Alison J. Parker, Philip Gardiner, Peter J. H. Webborn and Robert J. Riley
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1365-1374; DOI: https://doi.org/10.1124/dmd.107.019455

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Research ArticleArticle

Prediction of the Pharmacokinetics of Atorvastatin, Cerivastatin, and Indomethacin Using Kinetic Models Applied to Isolated Rat Hepatocytes

Stuart W. Paine, Alison J. Parker, Philip Gardiner, Peter J. H. Webborn and Robert J. Riley
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1365-1374; DOI: https://doi.org/10.1124/dmd.107.019455
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