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Research ArticleArticle

Bridging In Vitro and In Vivo Metabolism and Transport of Faldaprevir in Human Using a Novel Cocultured Human Hepatocyte System, HepatoPac

Diane Ramsden, Donald J. Tweedie, Tom S. Chan, Mitchell E. Taub and Yongmei Li
Drug Metabolism and Disposition March 2014, 42 (3) 394-406; DOI: https://doi.org/10.1124/dmd.113.055897
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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Tom S. Chan
Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
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Mitchell E. Taub
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

An increased appreciation of the importance of transporter and enzyme interplay in drug clearance and a desire to delineate these mechanisms necessitates the utilization of models that contain a full complement of enzymes and transporters at physiologically relevant activities. Additionally, the development of drugs with longer half-lives requires in vitro systems with extended incubation times that allow characterization of metabolic pathways for low-clearance drugs. A recently developed coculture hepatocyte model, HepatoPac, has been applied to meet these challenges. Faldaprevir is a drug in late-stage development for the treatment of hepatitis C. Faldaprevir is a low-clearance drug with the somewhat unique characteristic of being slowly metabolized, producing two abundant hydroxylated metabolites (M2a and M2b) in feces (∼40% of the dose) without exhibiting significant levels of circulating metabolites in humans. The human HepatoPac model was investigated to characterize the metabolism and transport of faldaprevir. In human HepatoPac cultures, M2a and M2b were the predominant metabolites formed, with extents of formation comparable to in vivo. Direct glucuronidation of faldaprevir was shown to be a minor metabolic pathway. HepatoPac studies also demonstrated that faldaprevir is concentrated in liver with active uptake by multiple transporters (including OATP1B1 and Na+-dependent transporters). Overall, human HepatoPac cultures provided valuable insights into the metabolism and disposition of faldaprevir in humans and demonstrated the importance of enzyme and transporter interplay in the clearance of the drug.

Footnotes

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

  • dx.doi.org/10.1124/dmd.113.055897.

  • 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 Transport of FDV with Human HepatoPac

Diane Ramsden, Donald J. Tweedie, Tom S. Chan, Mitchell E. Taub and Yongmei Li
Drug Metabolism and Disposition March 1, 2014, 42 (3) 394-406; DOI: https://doi.org/10.1124/dmd.113.055897

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Research ArticleArticle

Metabolism and Transport of FDV with Human HepatoPac

Diane Ramsden, Donald J. Tweedie, Tom S. Chan, Mitchell E. Taub and Yongmei Li
Drug Metabolism and Disposition March 1, 2014, 42 (3) 394-406; DOI: https://doi.org/10.1124/dmd.113.055897
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