drug-protein binding
DESCRIPTION
Quantitative Pharmacokinetics. Drug-Protein Binding. Dr. Chalet Tan. 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: - PowerPoint PPT PresentationTRANSCRIPT
1
Drug-Protein Binding
Dr. Chalet Tan
Quantitative Pharmacokinetics
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
albumin: binds mostly to acidic drugs 1-acid glycoprotein: binds mostly to basic drugslipoproteins: binds mostly to neutral drugs
TABLE 5-3
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
at equilibrium, Cu = CuT
Drug-Protein Binding Affects Drug Distribution
10
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.
11
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.
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)
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
control patients with chronic hepatic disease
V of propranolol is proportional to its fu in plasma.
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?