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Research ArticleArticle

Functional Maturation of Drug Transporters in the Developing, Neonatal, and Postnatal Kidney

Derina E. Sweeney, Volker Vallon, Timo Rieg, Wei Wu, Thomas F. Gallegos and Sanjay K. Nigam
Molecular Pharmacology July 2011, 80 (1) 147-154; DOI: https://doi.org/10.1124/mol.110.070680
Derina E. Sweeney
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Volker Vallon
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Timo Rieg
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Wei Wu
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Thomas F. Gallegos
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Sanjay K. Nigam
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Abstract

Because renal function in newborns is immature, the pharmacokinetics of drugs administered to neonates vary significantly from adult patients. The establishment of drug transport systems is a key process in the functional maturation of the nephron. However, a thorough examination of the expression of the main drug transporters in the kidney throughout all stages of development (embryonic, postnatal, and mature) has yet to be carried out, and the functional (physiological) impact is not well understood. Using time-series microarray data, we analyzed the temporal behavior of mRNA levels for a wide range of SLC and ABC transporters in the rodent kidney throughout a developmental time series. We find dynamic increases between the postnatal and mature stages of development for a number of transporters, including the proximal tubule-specific drug and organic anion transporters (OATs) OAT1 (SLC22a6) and OAT3 (SLC22a8). The OATs are the major multispecific basolateral drug, toxin, and metabolite transporters in the proximal tubule responsible for handling of many drugs, as well as the prototypical OAT substrate para-aminohippurate (PAH). We therefore performed specific in vivo pharmacokinetic analysis of the transport of PAH in postnatal and maturing rodent kidney. We show that there is a 4-fold increase in PAH clearance during this period. Clearance studies in Oat1 and Oat3 knockouts confirm that, as in the adult, Oat1 is the principle transporter of PAH in the postnatal kidney. The substantial differences observed supports the need for better understanding of pharmacokinetics in the newborn and juvenile kidney compared with the adult kidney at the basic and clinical level.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL94728]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants P30-DK079337, DK079784]; the National Institutes of Health National Institute of General Medical Sciences [Grant GM088824]; the Department of Veterans Affairs; the American Heart Association [Grant 10SDG2610034]; and the American Society of Nephrology Carl W. Gottschalk Research Scholar Grant.

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

    doi:10.1124/mol.110.070680.

  • ABBREVIATIONS:

    ABC
    ATP-binding cassette
    OAT
    organic anion transporter
    PAH
    para-aminohippurate
    SLC
    solute carrier
    GUDMAP
    genitourinary development molecular anatomy project
    UT
    ureteric tip
    PT
    proximal tubules
    RC
    renal corpuscle
    MM
    metanephric mesenchyme
    CM
    cap mesenchyme
    RV
    renal vesicle
    SS
    S-shaped body
    AH
    loop of Henle
    UB
    ureteric bud
    CCD
    cortical collecting duct
    MC
    medullary collecting duct
    UR
    urothelium
    US
    ureteral smooth muscle
    MI
    medullary interstitium
    P0
    birth
    CI
    cortical interstitium
    e
    embryonic day
    WT
    wild type
    NS
    not significant.

  • Received December 17, 2010.
  • Accepted April 14, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

Functional Maturation of Drug Transporters in the Developing, Neonatal, and Postnatal Kidney

Derina E. Sweeney, Volker Vallon, Timo Rieg, Wei Wu, Thomas F. Gallegos and Sanjay K. Nigam
Molecular Pharmacology July 1, 2011, 80 (1) 147-154; DOI: https://doi.org/10.1124/mol.110.070680

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Research ArticleArticle

Functional Maturation of Drug Transporters in the Developing, Neonatal, and Postnatal Kidney

Derina E. Sweeney, Volker Vallon, Timo Rieg, Wei Wu, Thomas F. Gallegos and Sanjay K. Nigam
Molecular Pharmacology July 1, 2011, 80 (1) 147-154; DOI: https://doi.org/10.1124/mol.110.070680
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