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Research ArticleArticle

Generating an In Vitro–In Vivo Correlation for Metabolism and Liver Enrichment of a Hepatitis C Virus Drug, Faldaprevir, Using a Rat Hepatocyte Model (HepatoPac)

Diane Ramsden, Donald J. Tweedie, Roger St. George, Lin-Zhi Chen and Yongmei Li
Drug Metabolism and Disposition March 2014, 42 (3) 407-414; DOI: https://doi.org/10.1124/dmd.113.055947
Diane Ramsden
Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
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Donald J. Tweedie
Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
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Roger St. George
Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
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Lin-Zhi Chen
Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
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Yongmei Li
Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
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Abstract

Hepatocytes provide an integrated model to study drug metabolism and disposition. As a result of a loss of polarity or a significant decrease in the expression of enzymes and transporters, suspended and sandwich-cultured hepatocytes have limitations in determining hepatocellular drug concentrations. Underprediction of the extent of glucuronidation is also a concern for these hepatocyte models. Faldaprevir is a hepatitis C virus protease inhibitor in late-stage development that has demonstrated significant liver enrichment in in vivo rat models based on quantitative whole-body autoradiography (QWBA) and liver-to-plasma area under-the-curve ratio. In bile duct cannulated rats, the primary biliary metabolite was a glucuronide. Owing to ethical concerns, it is difficult to assess liver enrichment in humans, and a lack of in vitro and in vivo correlation of glucuronidation has been reported. The current study was conducted to verify whether a hepatocyte model, rat HepatoPac, could overcome some of these limitations and provide validity for follow-up studies with human HepatoPac. With rat HepatoPac, liver enrichment values averaged 34-fold and were consistent with rat QWBA (26.8-fold) and in vivo data (42-fold). In contrast, liver enrichment in suspended hepatocytes was only 2.8-fold. Furthermore, the extent of faldaprevir glucuronidation in HepatoPac studies was in agreement with in vivo results, with glucuronidation as the major pathway (96%). Suspended rat hepatocytes did not generate the glucuronide or two key hydroxylated metabolites that were observed in vivo. Overall, our studies suggest that HepatoPac is a promising in vitro model to predict in vivo liver enrichment and metabolism, especially for glucuronidation, and has demonstrated superiority over suspended hepatocytes.

Footnotes

    • Received November 8, 2013.
    • Accepted December 23, 2013.
  • This research was funded by Boehringer Ingelheim Pharmaceuticals, Inc.

  • dx.doi.org/10.1124/dmd.113.055947.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (3)
Drug Metabolism and Disposition
Vol. 42, Issue 3
1 Mar 2014
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Research ArticleArticle

Metabolism and Liver Enrichment of FDV in Rat Hepatocytes

Diane Ramsden, Donald J. Tweedie, Roger St. George, Lin-Zhi Chen and Yongmei Li
Drug Metabolism and Disposition March 1, 2014, 42 (3) 407-414; DOI: https://doi.org/10.1124/dmd.113.055947

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Research ArticleArticle

Metabolism and Liver Enrichment of FDV in Rat Hepatocytes

Diane Ramsden, Donald J. Tweedie, Roger St. George, Lin-Zhi Chen and Yongmei Li
Drug Metabolism and Disposition March 1, 2014, 42 (3) 407-414; DOI: https://doi.org/10.1124/dmd.113.055947
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