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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Preclinical and Clinical Evidence for the Collaborative Transport and Renal Secretion of an Oxazolidinone Antibiotic by Organic Anion Transporter 3 (OAT3/SLC22A8) and Multidrug and Toxin Extrusion Protein 1 (MATE1/SLC47A1)

Yurong Lai, Kathleen E. Sampson, Larissa M. Balogh, Timothy G. Brayman, Steven R. Cox, Wade J. Adams, Vikas Kumar and Jeffrey C. Stevens
Journal of Pharmacology and Experimental Therapeutics September 2010, 334 (3) 936-944; DOI: https://doi.org/10.1124/jpet.110.170753
Yurong Lai
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Kathleen E. Sampson
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Larissa M. Balogh
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Timothy G. Brayman
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Steven R. Cox
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Wade J. Adams
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Vikas Kumar
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Jeffrey C. Stevens
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Abstract

N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (PNU-288034), an oxazolidinone antibiotic, was terminated in phase I clinical development because of insufficient exposure. Analysis of the drug pharmacokinetic and elimination profiles suggested that PNU-288034 undergoes extensive renal secretion in humans. The compound was well absorbed and exhibited approximately linear pharmacokinetics in the oral dose range of 100 to 1000 mg in human. PNU-288034 was metabolically stable in liver microsomes across species, and unchanged drug was cleared in the urine by an apparent active renal secretion process in rat and monkey (two to four times glomerular filtration rate) but not dog. In vitro studies conducted to characterize the transporters involved demonstrated PNU-288034 uptake by human organic anion transporter 3 (OAT3; Km = 44 ± 5 μM) and human multidrug and toxin extrusion protein 1 (hMATE1; Km = 340 ± 55 μM). The compound was also transported by multidrug resistance P-glycoprotein and breast cancer resistance protein. In contrast, human organic cation transporter 2, human OAT1, and hMATE2-K did not transport PNU-288034. Coadministration of PNU-288034 and the OAT3 inhibitor probenecid significantly increased PNU-288034 plasma area under the curve (170%) and reduced both plasma and renal clearance in monkey. Coadministration of PNU-288034 and cimetidine, a MATE1 inhibitor, also reduced plasma clearance in rat to a rate comparable with probenecid coadministration. Collectively, our results demonstrated a strong in vitro–in vivo correlation for active renal secretion coordinated through the vectorial transport process of OAT3 and MATE1, which ultimately resulted in limiting the systemic exposure of PNU-288034.

Footnotes

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

    doi:10.1124/jpet.110.170753.

  • ABBREVIATIONS:

    PNU-288034
    N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide
    P-gp
    P-glycoprotein
    BCRP
    breast cancer resistance protein
    OCT
    organic cation transporter
    OAT
    organic anion transporter
    hOAT
    human OAT
    MATE
    multidrug and toxin extrusion protein
    hMATE
    human MATE
    GFR
    glomerular filtration rate
    Cmax
    maximum concentration
    Tmax
    time to Cmax
    CL
    clearance
    AUC
    area under the curve
    DDI
    drug–drug interaction
    WT
    wild type
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    ACN
    acetonitrile
    SVC
    superior vena cava
    HEK
    human embryonic kidney
    HBSS
    Hanks' balanced salt solution
    MEM
    minimum essential medium
    FBS
    fetal bovine serum
    MDCK
    Madin-Darby canine kidney
    Papp
    apparent permeability
    MRT
    mean residence time
    PNU-100766
    (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.

  • Received May 26, 2010.
  • Accepted June 1, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 3
1 Jun 2023
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Preclinical and Clinical Evidence for the Collaborative Transport and Renal Secretion of an Oxazolidinone Antibiotic by Organic Anion Transporter 3 (OAT3/SLC22A8) and Multidrug and Toxin Extrusion Protein 1 (MATE1/SLC47A1)
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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Preclinical and Clinical Evidence for the Collaborative Transport and Renal Secretion of an Oxazolidinone Antibiotic by Organic Anion Transporter 3 (OAT3/SLC22A8) and Multidrug and Toxin Extrusion Protein 1 (MATE1/SLC47A1)

Yurong Lai, Kathleen E. Sampson, Larissa M. Balogh, Timothy G. Brayman, Steven R. Cox, Wade J. Adams, Vikas Kumar and Jeffrey C. Stevens
Journal of Pharmacology and Experimental Therapeutics September 1, 2010, 334 (3) 936-944; DOI: https://doi.org/10.1124/jpet.110.170753

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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Preclinical and Clinical Evidence for the Collaborative Transport and Renal Secretion of an Oxazolidinone Antibiotic by Organic Anion Transporter 3 (OAT3/SLC22A8) and Multidrug and Toxin Extrusion Protein 1 (MATE1/SLC47A1)

Yurong Lai, Kathleen E. Sampson, Larissa M. Balogh, Timothy G. Brayman, Steven R. Cox, Wade J. Adams, Vikas Kumar and Jeffrey C. Stevens
Journal of Pharmacology and Experimental Therapeutics September 1, 2010, 334 (3) 936-944; DOI: https://doi.org/10.1124/jpet.110.170753
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