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Research ArticleArticle

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

T. Eric Ballard, Shuai Wang, Loretta M. Cox, Mark A. Moen, Stacy Krzyzewski, Okechukwu Ukairo and R. Scott Obach
Drug Metabolism and Disposition February 2016, 44 (2) 172-179; DOI: https://doi.org/10.1124/dmd.115.066688
T. Eric Ballard
Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (T.E.B., S.W., L.M.C., M.A.M., R.S.O.); Hepregen Corporation, Medford, Massachusetts (S.K., O.U.),
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Shuai Wang
Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (T.E.B., S.W., L.M.C., M.A.M., R.S.O.); Hepregen Corporation, Medford, Massachusetts (S.K., O.U.),
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Loretta M. Cox
Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (T.E.B., S.W., L.M.C., M.A.M., R.S.O.); Hepregen Corporation, Medford, Massachusetts (S.K., O.U.),
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Mark A. Moen
Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (T.E.B., S.W., L.M.C., M.A.M., R.S.O.); Hepregen Corporation, Medford, Massachusetts (S.K., O.U.),
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Stacy Krzyzewski
Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (T.E.B., S.W., L.M.C., M.A.M., R.S.O.); Hepregen Corporation, Medford, Massachusetts (S.K., O.U.),
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Okechukwu Ukairo
Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (T.E.B., S.W., L.M.C., M.A.M., R.S.O.); Hepregen Corporation, Medford, Massachusetts (S.K., O.U.),
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R. Scott Obach
Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (T.E.B., S.W., L.M.C., M.A.M., R.S.O.); Hepregen Corporation, Medford, Massachusetts (S.K., O.U.),
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Abstract

Laboratory animal models are the industry standard for preclinical risk assessment of drug candidates. Thus, it is important that these species possess profiles of drug metabolites that are similar to those anticipated in human, since metabolites also could be responsible for biologic activities or unanticipated toxicity. Under most circumstances, preclinical species reflect human in vivo metabolites well; however, there have been several notable exceptions, and understanding and predicting these exceptions with an in vitro system would be very useful. Human micropatterned cocultured (MPCC) hepatocytes have been shown to recapitulate human in vivo qualitative metabolic profiles, but the same demonstration has not been performed yet for laboratory animal species. In this study, we investigated several compounds that are known to produce human-unique metabolites through CYP2C9, UGT1A4, aldehyde oxidase (AO), or N-acetyltransferase that were poorly covered or not detected at all in the selected preclinical species. To perform our investigation we used 24-well MPCC hepatocyte plates having three individual human donors and a single donor each of monkey, dog, and rat to study drug metabolism at four time points per species. Through the use of the multispecies MPCC hepatocyte system, the metabolite profiles of the selected compounds in human donors effectively captured the qualitative in vivo metabolite profile with respect to the human metabolite of interest. Human-unique metabolites that were not detected in vivo in certain preclinical species (normally dog and rat) were also not generated in the corresponding species in vitro, confirming that the MPCC hepatocytes can provide an assessment of preclinical species metabolism. From these results, we conclude that multispecies MPCC hepatocyte plates could be used as an effective in vitro tool for preclinical understanding of species metabolism relative to humans and aid in the choice of appropriate preclinical models.

Footnotes

    • Received August 17, 2015.
    • Accepted November 19, 2015.
  • ↵1 Current affiliation: University of Illinois at Chicago, Chicago, Illinois.

  • ↵2 Current affiliation: Ipsen Biosciences, Inc., Cambridge, Massachusetts.

  • dx.doi.org/10.1124/dmd.115.066688.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (2)
Drug Metabolism and Disposition
Vol. 44, Issue 2
1 Feb 2016
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Research ArticleArticle

Multispecies MPCC Metabolite Profiling

T. Eric Ballard, Shuai Wang, Loretta M. Cox, Mark A. Moen, Stacy Krzyzewski, Okechukwu Ukairo and R. Scott Obach
Drug Metabolism and Disposition February 1, 2016, 44 (2) 172-179; DOI: https://doi.org/10.1124/dmd.115.066688

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Research ArticleArticle

Multispecies MPCC Metabolite Profiling

T. Eric Ballard, Shuai Wang, Loretta M. Cox, Mark A. Moen, Stacy Krzyzewski, Okechukwu Ukairo and R. Scott Obach
Drug Metabolism and Disposition February 1, 2016, 44 (2) 172-179; DOI: https://doi.org/10.1124/dmd.115.066688
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