Pharmaceutical Research

, 36:30 | Cite as

Pharmacokinetic and Pharmacodynamic Considerations for Drugs Binding to Alpha-1-Acid Glycoprotein

  • Sherri A. SmithEmail author
  • Nigel J. Waters
Expert Review


According to the free drug hypothesis only the unbound drug is available to act at physiological sites of action, and as such the importance of plasma protein binding primarily resides in its impact on pharmacokinetics and pharmacodynamics. Of the major plasma proteins, alpha-1-acid glycoprotein (AAG) represents an intriguing one primarily due to the high affinity, low capacity properties of this protein. In addition, there are marked species and age differences in protein expression, homology and drug binding affinity. As such, a thorough understanding of drug binding to AAG can help aid and improve the translation of pharmacokinetic/pharmacodynamic (PK/PD) relationships from preclinical species to human as well as adults to neonates. This review provides a comprehensive overview of our current understanding of the biochemistry of AAG; endogenous function, impact of disease, utility as a biomarker, and impact on PK/PD. Experimental considerations are discussed as well as recommendations for understanding the potential impact of AAG on PK through drug discovery and early development.


alpha-1-acid glycoprotein fraction unbound pharmacodynamics pharmacokinetics protein binding 



Acute phase protein

AAG, AGP, ORM, orosomucoid

Alpha-1-acid glycoprotein


Area under curve




Drug-drug interaction


Diethylhexyl phthalate


Fraction unbound


Human serum albumin


In vitro in vivo extrapolation


Equilibrium dissociation constant






Volume of distribution at steady-state


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Drug Metabolism, Pharmacokinetics and BioanalyticalH3 BiomedicineCambridgeUSA
  2. 2.Nonclinical DevelopmentRelay TherapeuticsCambridgeUSA

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