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Drug Metabolism & Disposition

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

In Vitro–In Vivo Correlation for Low-Clearance Compounds Using Hepatocyte Relay Method

Li Di, Karen Atkinson, Christine C. Orozco, Carrie Funk, Hui Zhang, Thomas S. McDonald, Beijing Tan, Jian Lin, Cheng Chang and R. Scott Obach
Drug Metabolism and Disposition December 2013, 41 (12) 2018-2023; DOI: https://doi.org/10.1124/dmd.113.053322
Li Di
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut
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Karen Atkinson
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut
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Christine C. Orozco
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut
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Carrie Funk
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut
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Hui Zhang
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut
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Thomas S. McDonald
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut
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Beijing Tan
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut
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Jian Lin
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut
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Cheng Chang
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut
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R. Scott Obach
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut
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Abstract

In vitro–in vivo correlation (IVIVC) of intrinsic clearance in preclinical species of rat and dog was established using the hepatocyte relay method to support high-confidence prediction of human pharmacokinetics for low-clearance compounds. Good IVIVC of intrinsic clearance was observed for most of the compounds, with predicted values within 2-fold of the observed values. The exceptions involved transporter-mediated uptake clearance or metabolizing enzymes with extensive extrahepatic contribution. This is the first assay available to address low clearance challenges in preclinical species for IVIVC in drug discovery. It extends the utility of the hepatocyte relay method in addressing low clearance issues.

Footnotes

    • Received June 17, 2013.
    • Accepted July 15, 2013.
  • dx.doi.org/10.1124/dmd.113.053322.

  • 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

IVIVC of Low Clearance

Li Di, Karen Atkinson, Christine C. Orozco, Carrie Funk, Hui Zhang, Thomas S. McDonald, Beijing Tan, Jian Lin, Cheng Chang and R. Scott Obach
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2018-2023; DOI: https://doi.org/10.1124/dmd.113.053322

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

IVIVC of Low Clearance

Li Di, Karen Atkinson, Christine C. Orozco, Carrie Funk, Hui Zhang, Thomas S. McDonald, Beijing Tan, Jian Lin, Cheng Chang and R. Scott Obach
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2018-2023; DOI: https://doi.org/10.1124/dmd.113.053322
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  • Clearance Prediction Using HepatoPac
  • In Vitro–In Vivo Correlation of P-gp Efflux Ratio
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