Quantitative Pharmacokinetics
Drug-Protein Binding
Dr. Chalet Tan
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Learning Objectives
 proteins that bind drugs and types of protein binding
 factors affecting drug-protein binding
 effect of protein binding on drug distribution
Required reading:
Tozer & Rowland, Introduction to Pharmacokinetics and
Pharmacodynamics, Chapter 5, p83-89.
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Relevance of Drug-Protein Binding to Drug Therapy
 protein-bound drugs are pharmacologically inactive
 protein-bound drugs does not cross cell membranes,
affecting:
 distribution

metabolism

excretion
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Types of Drug-Protein Binding
 reversible
• weak chemical bonds such as hydrogen bonds or van der
Waals forces
• occurs to most drugs
 irreversible
• covalent chemical bonds
• accounts for certain toxicities of drugs and carcinogens
e. g. high doses of acetaminophen
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Major Drug-Binding Proteins in Plasma
TABLE 5-3
albumin:
binds mostly to acidic drugs
a1-acid glycoprotein:
binds mostly to basic drugs
lipoproteins:
binds mostly to neutral drugs
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The fraction of unbound drug in
plasma varies widely among
drugs
0 ≤ fu ≤ 1
Figure 5-13
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Methods for Studying Drug-Protein Binding
 equilibrium dialysis
 ultracentrifuge
 gel chromatography
 electrophoresis
For the ease of chemical analysis, total
plasma
concentrations of drugs (instead of unbound drug
concentrations) are most commonly measured.
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Drug-Protein Binding Affects Drug Distribution
Figure 5-14
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Drug-Protein Binding Affects Drug Distribution
at equilibrium, Cu = CuT
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Drug-Protein Binding Affects Drug Distribution
V:
volume of distribution
Vp:
volume of the plasma
VT:
volume of the tissue
fu :
free fraction of the drug in the plasma
fuT : free fraction of the drug in the tissue
VT of a drug is dependent on its physicochemical properties.
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V and Volumes of Body Water
For a 70-kg healthy individual,
extracellular
plasma
3L
interstitial fluids
13 L
intracellular
26 L
Total
42 L
 V rarely correlates to a real volume.
 V of drugs with MW > 70 KD is close to 3 L.
 V of small MW drugs that are neither bound in plasma nor
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in tissue is between 16 – 42 L.
Factors Affecting Drug-Protein Binding
 drug
• physicochemical properties
• concentration
 protein
• physicochemical properties
• concentration
 displacement by co-administered drugs
e. g. increased free warfarin level when co-administered
with salicylic acid (displacer)
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Displacement may occur if:
 the drug (e. g. warfarin) is highly protein-bound; and
 the displacer (e. g. salicylic acid) occupies most of the
binding site.
Factors Affecting Drug-Protein Binding
 pathophysiological conditions of the patients
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V of propranolol is proportional to its fu in plasma.
control
patients with
chronic hepatic
disease
Figure 5-15
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Plasma Protein Binding Determines the Distribution
of Many Drugs
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V of Some Drugs Does Not Depend on Plasma
Protein Binding
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Furosemide and amiodarone have fu
between 0.02-0.04, an acidic and a
basic drug respectively. Yet, the
former has a V of 10 L and the latter
7000 L. What contributes to this
difference?
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