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Archives of Toxicology

, Volume 93, Issue 3, pp 615–621 | Cite as

Importance of in vitro conditions for modeling the in vivo dose in humans by in vitroin vivo extrapolation (IVIVE)

  • Engi Abdel Hady AlgharablyEmail author
  • Reinhold Kreutz
  • Ursula Gundert-Remy
Toxicokinetics and Metabolism

Abstract

In vitro studies are increasingly proposed to replace in vivo toxicity testing of substances. We set out to apply physiologically based pharmacokinetic (PBPK) modeling to predict the in vivo dose of amiodarone that leads to the same concentration–time profile in the supernatant and the cell lysate of cultured primary human hepatic cells (PHH). A PBPK human model was constructed based on the structure and tissue distribution of amiodarone in a rat model and using physiological human parameters. The predicted concentration–time profile in plasma was in agreement with human experimental data with the unbound fraction of amiodarone in plasma crucially affecting the goodness-of-fit. Using the validated kinetic model, we subsequently described the in vitro concentration–time data of amiodarone in PHH culture. However, this could be only appropriately modeled under conditions of zero protein binding and the very low clearance of the in vitro system in PHH culture. However, these represent unphysiological conditions and, thus, the main difference between the in vivo and the in vitro systems. Our results reveal that, for meaningful quantitative extrapolation from in vitro to in vivo conditions in PBPK studies, it is essential to avoid non-intended differences between these conditions. Specifically, clearance and protein binding, as demonstrated in our analysis of amiodarone modeling, are important parameters to consider.

Keywords

Pharmacokinetics Amiodarone Animal alternatives In silico Physiologically based pharmacokinetic modeling Hepatotoxicity 

Notes

Acknowledgements

We would like to thank Dr. E. Di Consiglio and Dr. E. Testai, Istituto Superiore di Sanità, Environment and Primary Prevention Dept., Mechanisms of Toxicity Unit, Rome, Italy, for providing us with the concentration–time data of amiodarone in the supernatant and the human hepatic cells. We also thank Dr. Yuan-Sheng Zhao for the support with the implementation of the rat model.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Engi Abdel Hady Algharably
    • 1
    • 2
    Email author
  • Reinhold Kreutz
    • 1
  • Ursula Gundert-Remy
    • 1
  1. 1.Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of HealthBerlinGermany
  2. 2.Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams UniversityCairoEgypt

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