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Rapid CommunicationAccelerated Communication

Assessment of a Micropatterned Hepatocyte Coculture System to Generate Major Human Excretory and Circulating Drug Metabolites

Wendy WeiWei Wang, Salman R. Khetani, Stacy Krzyzewski, David B. Duignan and R. Scott Obach
Drug Metabolism and Disposition October 2010, 38 (10) 1900-1905; DOI: https://doi.org/10.1124/dmd.110.034876
Wendy WeiWei Wang
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Salman R. Khetani
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Stacy Krzyzewski
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David B. Duignan
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R. Scott Obach
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Abstract

Metabolism is one of the important determinants of the overall disposition of drugs, and the profile of metabolites can have an impact on efficacy and safety. Predicting which drug metabolites will be quantitatively predominant in humans has become increasingly important in the research and development of new drugs. In this study, a novel micropatterned hepatocyte coculture system was evaluated for its ability to generate human in vivo metabolites. Twenty-seven compounds of diverse chemical structure and subject to a range of drug biotransformation reactions were assessed for metabolite profiles in the micropatterned coculture system using pooled cryopreserved human hepatocytes. The ability of this system to generate metabolites that are >10% of dose in excreta or >10% of total drug-related material in circulation was assessed and compared to previously reported data obtained in human hepatocyte suspensions, liver S-9 fraction, and liver microsomes. The micropatterned coculture system was incubated for up to 7 days without a change in medium, which offered an ability to generate metabolites for slowly metabolized compounds. The micropatterned coculture system generated 82% of the excretory metabolites that exceed 10% of dose and 75% of the circulating metabolites that exceed 10% of total circulating drug-related material, exceeds the performance of hepatocyte suspension incubations and other in vitro systems. Phase 1 and phase 2 metabolites were generated, as well as metabolites that arise via two or more sequential reactions. These results suggest that this in vitro system offers the highest performance among in vitro metabolism systems to predict major human in vivo metabolites.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.034876.

  • ABBREVIATIONS:

    ADME
    absorption, distribution, metabolism, and excretion
    HCM
    hepatocyte culture medium
    HPLC
    high-pressure liquid chromatography
    CJ-13610
    4-{3-[4-(2-methyl-imidazol-1-yl)-phenylsulfanyl]-phenyl}-tetrahydro-pyra-n-4-carboxylic acid amide
    CP-122721
    (2-methoxy-5-trifluoromethoxy-benzyl)-((2S,3S)-2-phenyl-piperidin-3-yl)-amine
    CP-533536
    (3-{[(4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid
    CP-547632
    3-(4-bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido ]-isothiazole-4-carboxylic acid amide
    CP-690550
    3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile.

  • Received June 7, 2010.
  • Accepted July 1, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (10)
Drug Metabolism and Disposition
Vol. 38, Issue 10
1 Oct 2010
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Rapid CommunicationAccelerated Communication

Assessment of a Micropatterned Hepatocyte Coculture System to Generate Major Human Excretory and Circulating Drug Metabolites

Wendy WeiWei Wang, Salman R. Khetani, Stacy Krzyzewski, David B. Duignan and R. Scott Obach
Drug Metabolism and Disposition October 1, 2010, 38 (10) 1900-1905; DOI: https://doi.org/10.1124/dmd.110.034876

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Rapid CommunicationAccelerated Communication

Assessment of a Micropatterned Hepatocyte Coculture System to Generate Major Human Excretory and Circulating Drug Metabolites

Wendy WeiWei Wang, Salman R. Khetani, Stacy Krzyzewski, David B. Duignan and R. Scott Obach
Drug Metabolism and Disposition October 1, 2010, 38 (10) 1900-1905; DOI: https://doi.org/10.1124/dmd.110.034876
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