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Research ArticleArticle

Data-Based Mathematical Modeling of Vectorial Transport across Double-Transfected Polarized Cells

Kilian Bartholomé, Maria Rius, Katrin Letschert, Daniela Keller, Jens Timmer and Dietrich Keppler
Drug Metabolism and Disposition September 2007, 35 (9) 1476-1481; DOI: https://doi.org/10.1124/dmd.107.015636
Kilian Bartholomé
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Maria Rius
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Katrin Letschert
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Daniela Keller
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Jens Timmer
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Dietrich Keppler
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Abstract

Vectorial transport of endogenous small molecules, toxins, and drugs across polarized epithelial cells contributes to their half-life in the organism and to detoxification. To study vectorial transport in a quantitative manner, an in vitro model was used that includes polarized MDCKII cells stably expressing the recombinant human uptake transporter OATP1B3 in their basolateral membrane and the recombinant ATP-driven efflux pump ABCC2 in their apical membrane. These double-transfected cells enabled mathematical modeling of the vectorial transport of the anionic prototype substance bromosulfophthalein (BSP) that has frequently been used to examine hepatobiliary transport. Time-dependent analyses of 3H-labeled BSP in the basolateral, intracellular, and apical compartments of cells cultured on filter membranes and efflux experiments in cells preloaded with BSP were performed. A mathematical model was fitted to the experimental data. Data-based modeling was optimized by including endogenous transport processes in addition to the recombinant transport proteins. The predominant contributions to the overall vectorial transport of BSP were mediated by OATP1B3 (44%) and ABCC2 (28%). Model comparison predicted a previously unrecognized endogenous basolateral efflux process as a negative contribution to total vectorial transport, amounting to 19%, which is in line with the detection of the basolateral efflux pump Abcc4 in MDCKII cells. Rate-determining steps in the vectorial transport were identified by calculating control coefficients. Data-based mathematical modeling of vectorial transport of BSP as a model substance resulted in a quantitative description of this process and its components. The same systems biology approach may be applied to other cellular systems and to different substances.

Footnotes

  • This work was supported by the German Cancer Research Center, Heidelberg, Germany; the program on systems biology of the Bundesministerium für Forschung und Technologie, Berlin, Germany [grants to J.T. (0313074A) and D.K. (31P3111)]; and the Wilhelm Sander Foundation, München, Germany (Grant 2004.101.1).

  • doi:10.1124/dmd.107.015636.

  • ABBREVIATIONS: OATP1B3, human organic anion-transporting polypeptide, member 1B3; ABCC2, human ATP-binding cassette transporter, subfamily C, member 2; MRP2, multidrug resistance protein 2; BSP, bromosulfophthalein; MDCKII, Madin-Darby canine kidney cells strain II; Abcc4, canine ATP-binding cassette transporter, subfamily C, member 4; ABCC3, human ATP-binding cassette transporter, subfamily C, member 3; Endoex-ap, apical endogenous efflux transporter; Endoex-bl, basolateral endogenous efflux transporter; Endoin-bl, basolateral endogenous uptake transporter.

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

    • Received March 4, 2007.
    • Accepted May 30, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (9)
Drug Metabolism and Disposition
Vol. 35, Issue 9
1 Sep 2007
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Research ArticleArticle

Data-Based Mathematical Modeling of Vectorial Transport across Double-Transfected Polarized Cells

Kilian Bartholomé, Maria Rius, Katrin Letschert, Daniela Keller, Jens Timmer and Dietrich Keppler
Drug Metabolism and Disposition September 1, 2007, 35 (9) 1476-1481; DOI: https://doi.org/10.1124/dmd.107.015636

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Research ArticleArticle

Data-Based Mathematical Modeling of Vectorial Transport across Double-Transfected Polarized Cells

Kilian Bartholomé, Maria Rius, Katrin Letschert, Daniela Keller, Jens Timmer and Dietrich Keppler
Drug Metabolism and Disposition September 1, 2007, 35 (9) 1476-1481; DOI: https://doi.org/10.1124/dmd.107.015636
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