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The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery

Nature Reviews Drug Discovery volume 9, pages 929939 (2010) | Download Citation

Abstract

Data from in vitro plasma protein binding experiments that determine the fraction of protein-bound drug are frequently used in drug discovery to guide structure design and to prioritize compounds for in vivo studies. However, we consider that these practices are usually misleading, because in vivo efficacy is determined by the free (unbound) drug concentration surrounding the therapeutic target, not by the free drug fraction. These practices yield no enhancement of the in vivo free drug concentration. So, decisions based on free drug fraction could result in the wrong compounds being advanced through drug discovery programmes. This Perspective provides guidance on the application of plasma protein binding information in drug discovery.

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Acknowledgements

The authors would like to thank B. Harrison, G. Carter, O. McConnell, J. Butera, T. Mansour, M. Troutman, J. Liras and T. Liston for their support and leadership.

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Affiliations

  1. Dennis A. Smith is at the Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9UJ, UK.

    • Dennis A. Smith
  2. Li Di is at the Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA.

    • Li Di
  3. Edward H. Kerns is at Discovery ADME, 20 Hampton Court, Skillman, New Jersey 08558, USA.

    • Edward H. Kerns

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The authors declare no competing financial interests.

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Correspondence to Li Di.

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https://doi.org/10.1038/nrd3287

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