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Evaluation of Tissue Binding in 3 Tissues Across 5 Species, and Prediction of Volume of Distribution from Plasma Protein and Tissue Binding

Frederick Hsu, Ivy Chen and Fabio Broccatelli
Drug Metabolism and Disposition February 2, 2021, DMD-AR-2020-000337; DOI: https://doi.org/10.1124/dmd.120.000337
Frederick Hsu
1Drug Metabolism and Pharmacokinetics, Genentech, United States of America
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Ivy Chen
2Genentech, United States of America
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Fabio Broccatelli
3DMPK, Genentech, United States of America
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  • ORCID record for Fabio Broccatelli
  • For correspondence: fabio.broccatelli@gmail.com
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Abstract

Volume of distribution (Vd) is a primary pharmacokinetic parameter used to calculate the half-life and plasma concentration-time profile of drugs. Numerous models have been relatively successful in predicting Vd, but the model developed by Korzekwa and Nagar is of particular interest because it utilizes plasma protein binding and microsomal binding data, both of which are readily available in vitro parameters. Here, Korzekwa and Nagar's model was validated and expanded upon using external and internal datasets. Tissue binding, plasma protein binding, Vd, physiochemical, and physiological datasets were procured from literature and Genentech's internal database. First, we investigated the hypothesis that tissue binding is primarily governed by passive processes that depend on the lipid composition of the tissue type. The fraction unbound in tissues (futissue)was very similar across human, rat, and mouse. In addition, we showed that dilution factors could be generated from non-linear regression so that one futissue value could be used to estimate another one regardless of species. More importantly, results suggested that microsomes could serve as a surrogate for tissue binding. We applied the parameters from Korzekwa and Nagar's Vd model to two distinct liver microsomal datasets and found remarkably close statistical results. Brain and lung datasets also accurately predicted Vd, further validating the model. Vd prediction accuracy for compounds with LogD7.4 > 1 significantly outperformed that of more hydrophilic compounds. Finally, human Vd predictions from Korzekwa and Nagar's model appear to be as accurate as rat allometry and slightly less accurate than dog and cyno allometry.

Significance Statement We showed that tissue binding is comparable in three tissues across species and the fraction unbound in tissue can be interconverted with a dilution factor. In addition, we applied internal and external datasets to the volume of distribution model developed by Korzekwa and Nagar and found comparable Vd prediction accuracy between the Vd model and allometry. Our findings could potentially accelerate the drug R&D process by reducing the amount of resources associated with in vitro binding and animal experiments.

  • drug distribution
  • microsomes
  • plasma protein binding
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (3)
Drug Metabolism and Disposition
Vol. 49, Issue 3
1 Mar 2021
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Predicting Volume of Distribution from In Vitro Parameters

Frederick Hsu, Ivy Chen and Fabio Broccatelli
Drug Metabolism and Disposition February 2, 2021, DMD-AR-2020-000337; DOI: https://doi.org/10.1124/dmd.120.000337

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OtherArticle

Predicting Volume of Distribution from In Vitro Parameters

Frederick Hsu, Ivy Chen and Fabio Broccatelli
Drug Metabolism and Disposition February 2, 2021, DMD-AR-2020-000337; DOI: https://doi.org/10.1124/dmd.120.000337
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