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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 drugslipoproteins: 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 distributionVp: volume of the plasmaVT: volume of the tissuefu : free fraction of the drug in the plasmafuT : 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 WaterFor a 70-kg healthy individual,

extracellular plasma 3 L interstitial fluids 13 L

intracellular 26 LTotal 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?