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Research ArticleArticle

Inhibition of Hepatic Organic Anion-Transporting Polypeptide by RNA Interference in Sandwich-Cultured Human Hepatocytes: An In Vitro Model to Assess Transporter-Mediated Drug-Drug Interactions

Mingxiang Liao, Arek R. Raczynski, Michael Chen, Bei-Ching Chuang, Qing Zhu, Rob Shipman, Jodi Morrison, David Lee, Frank W. Lee, Suresh K. Balani and Cindy Q. Xia
Drug Metabolism and Disposition September 2010, 38 (9) 1612-1622; DOI: https://doi.org/10.1124/dmd.110.032995
Mingxiang Liao
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Arek R. Raczynski
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Michael Chen
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Bei-Ching Chuang
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Qing Zhu
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Rob Shipman
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Jodi Morrison
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David Lee
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Frank W. Lee
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Suresh K. Balani
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Cindy Q. Xia
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Abstract

Organic anion-transporting polypeptides (OATPs), members of the SLCO/SLC21 family, mediate the transport of various endo- and xenobiotics. In human liver, OATP1B1, 1B3, and 2B1 are located at the basolateral membrane of hepatocytes and are involved in hepatic drug uptake and biliary elimination. Clinically significant drug-drug interactions (DDIs) mediated by hepatic OATPs have drawn great attention from clinical practitioners and researchers. However, there are considerable challenges to prospectively understanding the extent of OATP-mediated DDIs because of the lack of specific OATP inhibitors or substrates and the limitations of in vitro tools. In the present study, a novel RNA interference knockdown sandwich-cultured human hepatocyte model was developed and validated. Quantitative polymerase chain reaction, microarray and immunoblotting analyses, along with uptake assays, illustrated that the expression and transport activity of hepatic OATPs were reduced by small interfering (siRNA) efficiently and specifically in this model. Although OATP siRNA decreased only 20 to 30% of the total uptake of cerivastatin into human hepatocytes, it caused a 50% reduction in cerivastatin metabolism, which was observed by monitoring the formation of the two major metabolites of cerivastatin. The results suggest that coadministration of a drug that is a hepatic OATP inhibitor could significantly alter the pharmacokinetic profile of cerivastatin in clinical studies. Further studies with this novel model demonstrated that OATP and cytochrome P450 have a synergistic effect on cerivastatin-gemfibrozil interactions. The siRNA knockdown sandwich-cultured human hepatocytes may provide a new powerful model for evaluating DDIs.

Footnotes

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

    doi:10.1124/dmd.110.032995.

  • ABBREVIATIONS:

    OATP
    organic anion-transporting polypeptide
    DDI
    drug-drug interaction
    AUC
    area under the concentration-time curve
    P450
    cytochrome P450
    DMEM
    Dulbecco's modified Eagle's medium
    E3S
    estrone-3-sulfate
    siRNA
    small interfering RNA
    PCR
    polymerase chain reaction
    aRNA
    amplified RNA
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    SSC
    standard saline citrate
    HBSS
    Hanks' balanced salt solution
    KHB
    Krebs-Henseleit buffer
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    ADME
    absorption, distribution, metabolism, and elimination.

  • Received February 26, 2010.
  • Accepted June 1, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (9)
Drug Metabolism and Disposition
Vol. 38, Issue 9
1 Sep 2010
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Research ArticleArticle

Inhibition of Hepatic Organic Anion-Transporting Polypeptide by RNA Interference in Sandwich-Cultured Human Hepatocytes: An In Vitro Model to Assess Transporter-Mediated Drug-Drug Interactions

Mingxiang Liao, Arek R. Raczynski, Michael Chen, Bei-Ching Chuang, Qing Zhu, Rob Shipman, Jodi Morrison, David Lee, Frank W. Lee, Suresh K. Balani and Cindy Q. Xia
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1612-1622; DOI: https://doi.org/10.1124/dmd.110.032995

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Research ArticleArticle

Inhibition of Hepatic Organic Anion-Transporting Polypeptide by RNA Interference in Sandwich-Cultured Human Hepatocytes: An In Vitro Model to Assess Transporter-Mediated Drug-Drug Interactions

Mingxiang Liao, Arek R. Raczynski, Michael Chen, Bei-Ching Chuang, Qing Zhu, Rob Shipman, Jodi Morrison, David Lee, Frank W. Lee, Suresh K. Balani and Cindy Q. Xia
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1612-1622; DOI: https://doi.org/10.1124/dmd.110.032995
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