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Use of partition coefficients in flow-limited physiologically-based pharmacokinetic modeling

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Abstract

Permeability-limited two-subcompartment and flow-limited, well-stirred tank tissue compartment models are routinely used in physiologically-based pharmacokinetic modeling. Here, the permeability-limited two-subcompartment model is used to derive a general flow-limited case of a two-subcompartment model with the well-stirred tank being a specific case where tissue fractional blood volume approaches zero. The general flow-limited two-subcompartment model provides a clear distinction between two partition coefficients typically used in PBPK: a biophysical partition coefficient and a well-stirred partition coefficient. Case studies using diazepam and cotinine demonstrate that, when the well-stirred tank is used with a priori predicted biophysical partition coefficients, simulations overestimate or underestimate total organ drug concentration relative to flow-limited two-subcompartment model behavior in tissues with higher fractional blood volumes. However, whole-body simulations show predicted drug concentrations in plasma and lower fractional blood volume tissues are relatively unaffected. These findings point to the importance of accurately determining tissue fractional blood volume for flow-limited PBPK modeling. Simulations using biophysical and well-stirred partition coefficients optimized with flow-limited two-subcompartment and well-stirred models, respectively, lead to nearly identical fits to tissue drug distribution data. Therefore, results of whole-body PBPK modeling with diazepam and cotinine indicate both flow-limited models are appropriate PBPK tissue models as long as the correct partition coefficient is used: the biophysical partition coefficient is for use with two-subcompartment models and the well-stirred partition coefficient is for use with the well-stirred tank model.

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Acknowledgments

This work was supported by NIH grant GM094503. MDT is supported by NIH training grant HL007852. The authors thank Dr. Malcolm Rowland (Professor Emeritus, University of Manchester) and Dr. Ivelina Gueorguieva (Eli Lilly and Company, UK) for kindly sharing the diazepam rat dataset. We are also grateful for helpful comments from reviewers.

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Authors and Affiliations

  1. Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Matthew D. Thompson & Daniel A. Beard

  2. CFD Research Corporation, Huntsville, AL, USA

    Fan Wu

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  1. Matthew D. Thompson
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  2. Daniel A. Beard
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  3. Fan Wu
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Correspondence to Daniel A. Beard.

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Thompson, M.D., Beard, D.A. & Wu, F. Use of partition coefficients in flow-limited physiologically-based pharmacokinetic modeling. J Pharmacokinet Pharmacodyn 39, 313–327 (2012). https://doi.org/10.1007/s10928-012-9252-6

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  • DOI: https://doi.org/10.1007/s10928-012-9252-6

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