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Research ArticleMetabolism, Transport, and Pharmacogenomics
Open Access

Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System

N. Tsamandouras, T. Kostrzewski, C. L. Stokes, L. G. Griffith, D. J. Hughes and M. Cirit
Journal of Pharmacology and Experimental Therapeutics January 2017, 360 (1) 95-105; DOI: https://doi.org/10.1124/jpet.116.237495
N. Tsamandouras
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (N.T., L.G.G., M.C.); CN Bio Innovations, Hertfordshire, United Kingdom (T.K., D.J.H.); and Stokes Consulting, Redwood City, California (C.L.S.)
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T. Kostrzewski
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (N.T., L.G.G., M.C.); CN Bio Innovations, Hertfordshire, United Kingdom (T.K., D.J.H.); and Stokes Consulting, Redwood City, California (C.L.S.)
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C. L. Stokes
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (N.T., L.G.G., M.C.); CN Bio Innovations, Hertfordshire, United Kingdom (T.K., D.J.H.); and Stokes Consulting, Redwood City, California (C.L.S.)
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L. G. Griffith
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (N.T., L.G.G., M.C.); CN Bio Innovations, Hertfordshire, United Kingdom (T.K., D.J.H.); and Stokes Consulting, Redwood City, California (C.L.S.)
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D. J. Hughes
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (N.T., L.G.G., M.C.); CN Bio Innovations, Hertfordshire, United Kingdom (T.K., D.J.H.); and Stokes Consulting, Redwood City, California (C.L.S.)
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M. Cirit
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (N.T., L.G.G., M.C.); CN Bio Innovations, Hertfordshire, United Kingdom (T.K., D.J.H.); and Stokes Consulting, Redwood City, California (C.L.S.)
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Abstract

In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from five different donors cultured in a perfused three-dimensional human liver microphysiological system, and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro–in vivo translation. For each donor, metabolic depletion profiles of six compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol, and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability [lactate dehydrogenase (LDH) release, albumin, and urea production]. Drug depletion data were analyzed with mixed-effects modeling. Substantial interdonor variability was observed with respect to gene expression levels, drug metabolism, and other measured hepatocyte functions. Specifically, interdonor variability in intrinsic metabolic clearance ranged from 24.1% for phenacetin to 66.8% for propranolol (expressed as coefficient of variation). Albumin, urea, LDH, and cytochrome P450 mRNA levels were identified as significant predictors of in vitro metabolic clearance. Predicted clearance values from the liver microphysiological system were correlated with the observed in vivo values. A population physiologically based pharmacokinetic model was developed for lidocaine to illustrate the translation of the in vitro output to the observed pharmacokinetic variability in vivo. Stochastic simulations with this model successfully predicted the observed clinical concentration-time profiles and the associated population variability. This is the first study of population variability in drug metabolism in the context of a microphysiological system and has important implications for the use of these systems during the drug development process.

Footnotes

    • Received August 30, 2016.
    • Accepted October 17, 2016.
  • ↵1 N.T. and T.K. contributed equally to this work.

  • This work was supported by the DARPA Microphysiological Systems Program [Grant W911NF-12-2-0039] and the National Institutes of Health Microphysiological Systems Program [Grant 4-UH3-TR000496-03].

  • dx.doi.org/10.1124/jpet.116.237495.

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

  • Copyright © 2016 by The Author(s)

This is an open access article distributed under the CC BY-NC Attribution 4.0 International license.

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Journal of Pharmacology and Experimental Therapeutics: 360 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 360, Issue 1
1 Jan 2017
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Assessment of Variability in Drug Metabolism with Liver MPS

N. Tsamandouras, T. Kostrzewski, C. L. Stokes, L. G. Griffith, D. J. Hughes and M. Cirit
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 95-105; DOI: https://doi.org/10.1124/jpet.116.237495

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Assessment of Variability in Drug Metabolism with Liver MPS

N. Tsamandouras, T. Kostrzewski, C. L. Stokes, L. G. Griffith, D. J. Hughes and M. Cirit
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 95-105; DOI: https://doi.org/10.1124/jpet.116.237495
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