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Drug–protein binding: a critical review of analytical tools

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Abstract

The extent of drug binding to plasma proteins, determined by measuring the free active fraction, has a significant effect on the pharmacokinetics and pharmacodynamics of a drug. It is therefore highly important to estimate drug-binding ability to these macromolecules in the early stages of drug discovery and in clinical practice. Traditionally, equilibrium dialysis is used, and is presented as the reference method, but it suffers from many drawbacks. In an attempt to circumvent these, a vast array of different methods has been developed. This review focuses on the most important approaches used to characterize drug–protein binding. A description of the principle of each method with its inherent strengths and weaknesses is outlined. The binding affinity ranges, information accessibility, material consumption, and throughput are compared for each method. Finally, a discussion is included to help users choose the most suitable approach from among the wealth of methods presented.

Range of binding constants (log Ka) assessable by the main separative and non-separative analytical tools used to characterize drug-protein interactions. ED: equilibrium dialysis, UF: ultrafiltration, PAMPA: parallel artificial membrane permeability assay, HPAC/ZE: high-performance affinity chromatography/zonal elution approach, HPAC/FA: high-performance affinity chromatography/frontal analysis approach, ACE: affinity capillary electrophoresis (mobility shift assay), CE/FA: capillary electrophoresis/frontal analysis, Spectro.: spectroscopic assays, ITC: isothermal titration calorimetry, comp.: competition studies, titration: titration studies, DSC: differential scanning calorimetry, SPR: surface plasmon resonance-based assays.

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Abbreviations

ACE:

Affinity capillary electrophoresis (mobility shift assay)

AGP:

α1-Acid glycoprotein

BGE:

Background electrolyte

BSA:

Bovine serum albumin

CD:

Circular dichroism

CE:

Capillary electrophoresis

CE/FA:

Capillary electrophoresis/frontal analysis

CZE:

Capillary zone electrophoresis

D:

Drug

DP:

Drug–protein complex

DSC:

Differential scanning calorimetry

ED:

Equilibrium dialysis

FA:

Frontal analysis

FACCE:

Continuous capillary electrophoresis frontal analysis

HD:

Hummel–Dreyer method

HDL:

High-density lipoproteins

HPAC:

High-performance affinity chromatography

HSA:

Human serum albumin

IR:

Infrared

ISRP:

Internal-surface reversed phase

ITC:

Isothermal titration calorimetry

K a :

Association constant

K d :

Dissociation constant

k off :

Dissociation rate constant

k on :

Association rate constant

LC:

Liquid chromatography

LDL:

Low-density lipoproteins

LIF:

Laser-induced fluorescence

m :

Total number of different classes of binding sites

MS:

Mass spectrometry

n :

Number of binding sites with the same affinity per protein molecule

NMR:

Nuclear magnetic resonance

NSB:

Nonspecific binding

ORD:

Optical rotatory dispersion

P:

Protein

PAMPA:

Parallel artificial membrane assay

r :

Number of total drugs bound per protein

SEC:

Size-exclusion chromatography

SPR:

Surface plasmon resonance

UC:

Ultracentrifugation

UF:

Ultrafiltration

VACE:

Vacancy affinity capillary electrophoresis

VP:

Vacancy peak method

ZE:

Zonal elution

ΔCp:

Heat capacity change

ΔG :

Gibbs free energy

ΔH :

Enthalpy of the binding reaction

ΔS :

Entropy change

μ :

Electrophoretic mobility

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai E-Ansermet 30, 1211, Geneva 4, Switzerland

    Karine Vuignier, Julie Schappler, Jean-Luc Veuthey, Pierre-Alain Carrupt & Sophie Martel

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  1. Karine Vuignier
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  2. Julie Schappler
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  3. Jean-Luc Veuthey
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  4. Pierre-Alain Carrupt
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  5. Sophie Martel
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Corresponding author

Correspondence to Sophie Martel.

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Vuignier, K., Schappler, J., Veuthey, JL. et al. Drug–protein binding: a critical review of analytical tools. Anal Bioanal Chem 398, 53–66 (2010). https://doi.org/10.1007/s00216-010-3737-1

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  • DOI: https://doi.org/10.1007/s00216-010-3737-1

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