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Parenteral Delivery of HPβCD: Effects on Drug-HSA Binding

AAPS PharmSciTech volume 11, pages 1152–1158 (2010)Cite this article

Abstract

It is thought that cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin (HPβCD), will at high concentration affect pharmacokinetics of drugs through competitive binding with plasma proteins. Albumin is the major component of plasma proteins responsible for plasma protein binding. The purpose of this study was to evaluate in vitro the competitive binding of drugs between human serum albumin (HSA) and HPβCD in isotonic pH 7.4 phosphate buffer saline solution (PBS) at ambient temperature. Eight model drugs were selected based on their physicochemical properties and ability to form complexes with HSA and HPβCD. The drug/HPβCD stability constants (K 1:1) were determined by the phase-solubility method and HSA/HPβCD competitive binding determined by an equilibrium dialysis method. Protein binding of drugs that are both strongly protein bound and have high affinity to HPβCD (i.e., have high K 1:1 value) is most likely to be affected by parenterally administered HPβCD. However, this in vitro study indicates that even for those drugs single parenteral dose of HPβCD has to be as high as 70 g to have detectable effect on their protein binding. Weakly protein bound drugs and drugs with low affinity towards HPβCD are insensitive to the cyclodextrin presence regardless their lipophilic properties.

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Acknowledgements

The financial support provided by Javelin Pharmaceuticals, Inc. (Cambridge, USA) is gratefully acknowledged by the authors.

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Affiliations

  1. Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107, Reykjavik, Iceland

    Sergey V. Kurkov, Thorsteinn Loftsson & Martin Messner

  2. Javelin Pharmaceuticals, Inc., 125 Cambridge Park Drive, Cambridge, Massachusetts, 021402, USA

    Donna Madden

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  1. Sergey V. Kurkov
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  2. Thorsteinn Loftsson
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  3. Martin Messner
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  4. Donna Madden
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Correspondence to Thorsteinn Loftsson.

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Kurkov, S.V., Loftsson, T., Messner, M. et al. Parenteral Delivery of HPβCD: Effects on Drug-HSA Binding. AAPS PharmSciTech 11, 1152–1158 (2010). https://doi.org/10.1208/s12249-010-9482-0

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KEY WORDS

  • 2-hydroxypropyl-β-cyclodextrin
  • competitive binding
  • equilibrium dialysis
  • human serum albumin
  • parenteral delivery
  • stability constant