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Research ArticleArticle

Application of Target-Mediated Drug Disposition Model to Small Molecule Heat Shock Protein 90 Inhibitors

Shinji Yamazaki, Zhongzhou Shen, Ying Jiang, Bill J. Smith and Paolo Vicini
Drug Metabolism and Disposition June 2013, 41 (6) 1285-1294; DOI: https://doi.org/10.1124/dmd.113.051490
Shinji Yamazaki
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, San Diego, California
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Zhongzhou Shen
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, San Diego, California
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Ying Jiang
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, San Diego, California
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Bill J. Smith
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, San Diego, California
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Paolo Vicini
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, San Diego, California
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Abstract

Replacement of hydrogen with fluorine within three pairs of structurally similar small molecule inhibitors of heat shock protein 90 (HSP90) resulted in differences in inhibition constants (Ki) in vitro as well as marked differences in rat intravenous pharmacokinetic profiles. The difference in pharmacokinetic profiles between lower and higher affinity inhibitors (LAIs and HAIs, respectively) was characterized by remarkably different estimates for steady-state volumes of distribution (Vss: 1.8–2.0 versus 10–13 l/kg) with comparable clearance estimates (3.2–3.5 l/h per kilogram). When the observed Vss estimates were compared with the values predicted with the tissue-composition-based model, the observed Vss estimates for HAIs were 4- to 8-fold larger than the predicted values, whereas the Vss values for LAIs were comparable. Accordingly, a negative relationship between in vitro HSP90 Ki versus in vivo Vss estimates was observed among these inhibitors. We therefore hypothesized that pharmacokinetic profiles of these inhibitors could be characterized by a target-mediated drug disposition (TMDD) model. In vivo equilibrium dissociation constant (KD) estimates for HAIs due to target binding by TMDD model with rapid binding approximation were 1–6 nM (equivalent to 0.3–2 nM free drug), which appeared comparable to the in vitro Ki estimates (2–3 nM). In vivo KD values of LAIs were not accurately determined by the TMDD model, likely due to nonspecific binding-dependent tissue distribution obscuring TMDD profiles. Overall, these results suggest that the observed large Vss estimates for potent HSP90 inhibitors are likely due to pharmacological target binding.

Footnotes

    • Received February 15, 2013.
    • Accepted April 4, 2013.
  • ↵1 Current affiliation: Dart NeuroScience, San Diego, California.

  • dx.doi.org/10.1124/dmd.113.051490.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (6)
Drug Metabolism and Disposition
Vol. 41, Issue 6
1 Jun 2013
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Research ArticleArticle

Target-Mediated Drug Disposition of HSP90 Inhibitors

Shinji Yamazaki, Zhongzhou Shen, Ying Jiang, Bill J. Smith and Paolo Vicini
Drug Metabolism and Disposition June 1, 2013, 41 (6) 1285-1294; DOI: https://doi.org/10.1124/dmd.113.051490

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Research ArticleArticle

Target-Mediated Drug Disposition of HSP90 Inhibitors

Shinji Yamazaki, Zhongzhou Shen, Ying Jiang, Bill J. Smith and Paolo Vicini
Drug Metabolism and Disposition June 1, 2013, 41 (6) 1285-1294; DOI: https://doi.org/10.1124/dmd.113.051490
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