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Drug-Protein Binding
Dr. Chalet Tan
Quantitative Pharmacokinetics
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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
albumin: binds mostly to acidic drugs
1-acid glycoprotein: binds mostly to basic drugs
lipoproteins: binds mostly to neutral drugs
TABLE 5-3
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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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at equilibrium, Cu = CuT
Drug-Protein Binding Affects Drug Distribution
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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
Drug-Protein Binding Affects Drug Distribution
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 3 L
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 in tissue is between 16 – 42 L.
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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.
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Factors Affecting Drug-Protein Binding
pathophysiological conditions of the patients
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control
patients with chronic hepatic disease
V of propranolol is proportional to its fu in plasma.
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?