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Research ArticleArticle

Mechanistic Modeling of Pitavastatin Disposition in Sandwich-Cultured Human Hepatocytes: A Proteomics-Informed Bottom-Up Approach

Anna Vildhede, André Mateus, Elin K. Khan, Yurong Lai, Maria Karlgren, Per Artursson and Maria C. Kjellsson
Drug Metabolism and Disposition April 2016, 44 (4) 505-516; DOI: https://doi.org/10.1124/dmd.115.066746
Anna Vildhede
Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.)
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André Mateus
Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.)
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Elin K. Khan
Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.)
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Yurong Lai
Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.)
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Maria Karlgren
Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.)
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Per Artursson
Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.)
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Maria C. Kjellsson
Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.)
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Abstract

Isolated human hepatocytes are commonly used to predict transporter-mediated clearance in vivo. Such predictions, however, do not provide estimations of transporter contributions and consequently do not allow predictions of the outcome resulting from a change in the activity of a certain transporter, for example, by inhibition or a genetic variant with reduced function. Pitavastatin is a drug that is heavily dependent on hepatic transporters for its elimination, and it is excreted mainly as unchanged drug in the bile. For this reason, pitavastatin was used as a model drug to demonstrate the applicability of a bottom-up approach to predict transporter-mediated disposition in sandwich-cultured human hepatocytes (SCHHs), allowing for the estimation of transporter contributions. Transport experiments in transfected human embryonic kidney cells (HEK293 cell lines) and inverted membrane vesicles overexpressing each of the relevant transport proteins were used to generate parameter estimates for the mechanistic model. By adjusting for differences in transporter abundance between the in vitro systems and individual SCHH batches, the model successfully predicted time profiles of medium and intracellular accumulation. Our predictions of pitavastatin bile accumulation could not be confirmed, however, because of a very low biliary excretion of pitavastatin in relation to the hepatic uptake in our SCHHs. This study is, to our knowledge, the first to successfully simulate transporter-mediated processes in a complex system such as SCHHs at the level of individual transport proteins using a bottom-up approach.

Footnotes

    • Received August 12, 2015.
    • Accepted February 1, 2016.
  • This work was supported by the Swedish Research Council [grant approval no. 2822]; the Lars Hierta Memorial Foundation; and O. E. and Edla Johansson’s Scientific Foundation.

  • dx.doi.org/10.1124/DMD.115.066746.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (4)
Drug Metabolism and Disposition
Vol. 44, Issue 4
1 Apr 2016
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Research ArticleArticle

A Bottom-Up Mechanistic Model for Hepatic Transport

Anna Vildhede, André Mateus, Elin K. Khan, Yurong Lai, Maria Karlgren, Per Artursson and Maria C. Kjellsson
Drug Metabolism and Disposition April 1, 2016, 44 (4) 505-516; DOI: https://doi.org/10.1124/dmd.115.066746

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Research ArticleArticle

A Bottom-Up Mechanistic Model for Hepatic Transport

Anna Vildhede, André Mateus, Elin K. Khan, Yurong Lai, Maria Karlgren, Per Artursson and Maria C. Kjellsson
Drug Metabolism and Disposition April 1, 2016, 44 (4) 505-516; DOI: https://doi.org/10.1124/dmd.115.066746
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