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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

Abstract

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.

KEY WORDS

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

Abbreviations

APP

Acute phase protein

AAG, AGP, ORM, orosomucoid

Alpha-1-acid glycoprotein

AUC

Area under curve

CL

Clearance

DDI

Drug-drug interaction

DEHP

Diethylhexyl phthalate

fu

Fraction unbound

HSA

Human serum albumin

IVIVE

In vitro in vivo extrapolation

KD

Equilibrium dissociation constant

PD

Pharmacodynamics

PK

Pharmacokinetics

Vss

Volume of distribution at steady-state

Notes

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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