Drug-Protein Binding

1. Quantitative Pharmacokinetics Drug-Protein Binding Dr. Chalet Tan

2. 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.

3. 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

4. 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

5. 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

6. The fraction of unbound drug in plasma varies widely among drugs 0 ≤ fu ≤ 1 Figure 5-13

7. 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.

8. Drug-Protein Binding Affects Drug Distribution Figure 5-14

9. Drug-Protein Binding Affects Drug Distribution at equilibrium,Cu = CuT

10. 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.

11. 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.

12. 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)

13. 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.

14. Factors Affecting Drug-Protein Binding • pathophysiological conditions of the patients

15. V of propranolol is proportional to its fu in plasma. control patients with chronic hepatic disease Figure 5-15

16. Plasma Protein Binding Determines the Distribution of Many Drugs

17. V of Some Drugs Does Not Depend on Plasma Protein Binding

18. 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? 18