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Rapid CommunicationAccelerated Communication

Differential Modulation of Cytochrome P450 Activity and the Effect of 1-Aminobenzotriazole on Hepatic Transport in Sandwich-Cultured Human Hepatocytes

Emi Kimoto, Robert Walsky, Hui Zhang, Yi-an Bi, Kevin M. Whalen, Young-Sun Yang, Collette Linder, Yongling Xiao, Ken Iseki, Katherine S. Fenner, Ayman F. El-Kattan and Yurong Lai
Drug Metabolism and Disposition February 2012, 40 (2) 407-411; DOI: https://doi.org/10.1124/dmd.111.039297
Emi Kimoto
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Robert Walsky
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Hui Zhang
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Yi-an Bi
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Kevin M. Whalen
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Young-Sun Yang
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Collette Linder
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Yongling Xiao
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Ken Iseki
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Katherine S. Fenner
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Ayman F. El-Kattan
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Yurong Lai
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Abstract

Sandwich-cultured human hepatocytes (SCHH) have been widely used for in vitro assessments of biliary clearance. However, the modulation of metabolism enzymes has not been fully evaluated in this system. The present study was therefore undertaken to determine the activity of cytochrome P450 (P450) 1A2, 2C8, 2C9, 2C19, 2D6, and 3A and to evaluate the impact of 1-aminobenzotriazole (ABT) on hepatic uptake and biliary excretion in SCHH. The SCHH maintained integrity and viability as determined by lactate dehydrogenase release and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assays conducted over the culture period. Although all assessed P450 activity decreased in day 2 SCHH, the extent of the decrease and the subsequent rebound in activity varied across the different isoforms. Day 5 CYP1A2 activity was approximately 2.5-fold higher than day 1 activity, whereas the CYP3A and CYP2C9 activities were 90 and 60% of the day 1 levels, respectively. In contrast, the initial CYP2C8, CYP2C19, and CYP2D6 activity losses did not rebound over the 5-day culture period. Furthermore, ABT was not found to have an effect, whether directly or indirectly as a P450 inactivator, with respect to the hepatic transport of rosuvastatin, atrovastatin, and midazolam in SCHH. Taken together, these results suggest that the SCHH model is a reliable tool to characterize hepatic uptake and biliary excretion. Due to the differential modulation of P450 activity, SCHH may not be considered a suitable tool for metabolic stability assessments with compounds predominantly cleared by certain P450 enzymes.

Footnotes

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

    doi:http://dx.doi.org/10.1124/dmd.111.039297.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    SCH
    sandwich-cultured hepatocytes
    SCHH
    sandwich-cultured human hepatocytes
    ABT
    1-aminobenzotriazole
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
    LDH
    lactate dehydrogenase
    CV
    coefficient of variation
    ANOVA
    analysis of variance.

  • Received March 3, 2011.
  • Accepted October 26, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (2)
Drug Metabolism and Disposition
Vol. 40, Issue 2
1 Feb 2012
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Rapid CommunicationAccelerated Communication

MODULATION OF P450 ACTIVITY IN SCHH

Emi Kimoto, Robert Walsky, Hui Zhang, Yi-an Bi, Kevin M. Whalen, Young-Sun Yang, Collette Linder, Yongling Xiao, Ken Iseki, Katherine S. Fenner, Ayman F. El-Kattan and Yurong Lai
Drug Metabolism and Disposition February 1, 2012, 40 (2) 407-411; DOI: https://doi.org/10.1124/dmd.111.039297

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Rapid CommunicationAccelerated Communication

MODULATION OF P450 ACTIVITY IN SCHH

Emi Kimoto, Robert Walsky, Hui Zhang, Yi-an Bi, Kevin M. Whalen, Young-Sun Yang, Collette Linder, Yongling Xiao, Ken Iseki, Katherine S. Fenner, Ayman F. El-Kattan and Yurong Lai
Drug Metabolism and Disposition February 1, 2012, 40 (2) 407-411; DOI: https://doi.org/10.1124/dmd.111.039297
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