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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)

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?