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Research ArticleArticle

Upcyte Human Hepatocytes: a Potent In Vitro Tool for the Prediction of Hepatic Clearance of Metabolically Stable Compounds

Michelle Schaefer, Gerhard Schänzle, Daniel Bischoff and Roderich D. Süssmuth
Drug Metabolism and Disposition March 2016, 44 (3) 435-444; DOI: https://doi.org/10.1124/dmd.115.067348
Michelle Schaefer
Department of Drug Discovery Support / Metabolism and Bioanalysis, Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (M.S., G.S., D.B.); and Department of Chemistry, Technische Universität Berlin, Berlin, Germany (R.D.S.)
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Gerhard Schänzle
Department of Drug Discovery Support / Metabolism and Bioanalysis, Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (M.S., G.S., D.B.); and Department of Chemistry, Technische Universität Berlin, Berlin, Germany (R.D.S.)
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Daniel Bischoff
Department of Drug Discovery Support / Metabolism and Bioanalysis, Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (M.S., G.S., D.B.); and Department of Chemistry, Technische Universität Berlin, Berlin, Germany (R.D.S.)
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Roderich D. Süssmuth
Department of Drug Discovery Support / Metabolism and Bioanalysis, Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (M.S., G.S., D.B.); and Department of Chemistry, Technische Universität Berlin, Berlin, Germany (R.D.S.)
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Abstract

In vitro models based on primary human hepatocytes (PHH) have been advanced for clearance (CL) prediction of metabolically stable compounds, representing state-of-the-art assay systems for drug discovery and development. Yet, limited cell availability and large interindividual variability of metabolic profiles remain shortcomings of PHH. Upcyte human hepatocytes (UHH) represent a novel hepatic cell system derived from PHH, exhibiting proliferative capacity for approximately 35 population doublings. UHH from three donors were evaluated during culture for up to 18 days, investigating relative mRNA expression and in situ enzyme activity of cytochrome P450s (P450s), UDP-glucuronosyltransferases, and sulfotransferases. Furthermore, UHH were used for predicting hepatic CL of 21 marketed low to intermediate CL drugs. In a typical experiment, expansion from 3.9 × 106 up to 8.5 × 107 cells was achieved during subculture. When maintained at confluence, transcripts of major P450s were expressed at donor-specific levels with sustained activities for the majority of isoforms, showing generally low CYP1A2 and high CYP2B6 activity levels. For donor 151-03, CL prediction based on depletion experiments resulted in an average fold error of 2.0, and 80% of compounds being predicted within twofold to in vivo CL for a subset of 10 low CL drugs. UHH showed sustained and consistent activity of drug-metabolizing enzymes (DME), resulting in highly reproducible CL prediction performance. In conclusion, UHH show promising potential as alternative to PHH for standardized in vitro applications in discovery research based on their stable, hepatocyte-like DME phenotype and virtually unlimited cell availability.

Footnotes

    • Received September 21, 2015.
    • Accepted December 23, 2015.
  • This work was supported by Boehringer Ingelheim Pharma.

  • dx.doi.org/10.1124/dmd.115.067348.

  • ↵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 (3)
Drug Metabolism and Disposition
Vol. 44, Issue 3
1 Mar 2016
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Research ArticleArticle

Upcyte Human Hepatocytes for Prediction of Human Clearance

Michelle Schaefer, Gerhard Schänzle, Daniel Bischoff and Roderich D. Süssmuth
Drug Metabolism and Disposition March 1, 2016, 44 (3) 435-444; DOI: https://doi.org/10.1124/dmd.115.067348

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Research ArticleArticle

Upcyte Human Hepatocytes for Prediction of Human Clearance

Michelle Schaefer, Gerhard Schänzle, Daniel Bischoff and Roderich D. Süssmuth
Drug Metabolism and Disposition March 1, 2016, 44 (3) 435-444; DOI: https://doi.org/10.1124/dmd.115.067348
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