1. Protein Binding of Drugs
Many drugs interact with plasma or tissue proteins or with other
macromolecules, such as melanin and DNA, to form a drug–
macromolecule complex. The formation of a drug protein complex is
often named drug–protein binding
AFROZ KHAN

2. • The rate of distribution of drug from blood to tissue depend on
the blood volume of organs. The more blood volume the
organ has, the faster the amount of drug diffused. Then there
is a redistribution in some organs. e.g. Thiopental is lipophilic
drug, and it diffuses into brain more quickly, then, redistribute
to the fat and other tissues.

3. • The concentration of drug at target organ should be measured
through the concentration of plasma. So the effect of the drug
may be estimated at target organ.

4. • Protein binding describes the ability of proteins to form bonds
with other substances, and most commonly refers to the
bonding of drugs to these molecules in blood plasma, red
blood cells, other components of the blood, and to tissue
membranes.

5. Biological relevance of drug binding
• The binding of drug to plasma (and tissue) proteins is a major
determinant of drug disposition (distribution)
• Binding has a very important effect on drug dynamics since
only the free (unbound) drug interacts with receptors

6. Binding of Drugs
• The proteins commonly involved in binding with drugs
are albumin, lipoproteins, and a1-acid-glycoprotein (AGP).
Acidic and neutral compounds will tend to bond with albumin,
which is basic, while basic substances will primarily bind to
the acidic AGP molecule.

7. • The bound drug is kept in the blood stream while the unbound
component may be metabolized or excreted, making it the
active part.
• So, if a drug is 95% bound to a binding protein and 5% is free,
that means that 5% is active in the system and causing
pharmacological effects.

8. • Drug–protein binding may be a reversible or an irreversible
process.
• Irreversible drug–protein binding is usually a result of
chemical activation of the drug, which then attaches strongly
to the protein or macromolecule by covalent chemical
bonding.
• Irreversible drug binding accounts for certain types of drug
toxicity that may occur over a long time period

9. • For example, the hepatotoxicity of high doses of
acetaminophen is due to the formation of reactive metabolite
intermediates that interact with liver proteins.

10. • Reversible drug–protein binding implies that the drug binds
the protein with weaker chemical bonds, such as hydrogen
bonds or vander Waals forces.

11. • A drug's efficiency may be affected by the degree to which it
binds to the proteins within blood plasma. The less bound a
drug is, the more efficiently it can traverse cell membranes or
diffuse. Common blood proteins that drugs bind to are human
serum albumin, lipoprotein, glycoprotein, α, β‚ and
γ globulins.

12. • A drug in blood exists in two forms: bound and unbound
• It is the unbound fraction which exhibits pharmacologic
effects. It is also the fraction that may be metabolized and or
excreted.
• For example, the "fraction bound" of the
anticoagulant warfarin is 97%. This means that of the amount
of warfarin in the blood, 97% is bound to plasma proteins. The
remaining 3% (the fraction unbound) is the fraction that is
actually active and may be excreted.

13. Drug interactions
• Using 2 drugs at the same time may affect each other's fraction
unbound.
• For example, assume that Drug A and Drug B are both protein-
bound drugs. If Drug A is given, it will bind to the plasma
proteins in the blood.
• If Drug B is also given, it can displace Drug A from the
protein, thereby increasing Drug A's fraction unbound. This
may increase the effects of Drug A, since only the unbound
fraction may exhibit activity.

14. Effect of Protein Binding on the
Apparent Volume of Distribution
• The extent of drug protein binding in the plasma or tissue
affects V D. Drugs that are highly bound to plasma proteins
have a low fraction of free drug
• The plasma protein-bound drug does not diffuse easily and is
therefore less extensively distributed to tissues

15. Relationship of Plasma Drug–Protein
Binding to Distribution and Elimination
• Drugs that are highly bound to plasma protein have reduced
overall drug clearance. For a drug that is metabolized mainly
by the liver, binding to plasma proteins prevents the drug from
entering the hepatocytes, resulting in reduced drug metabolism
by the liver.

16. Determinants of Protein Binding
Drug–protein binding is influenced by a number of
important factors, including the following:
1. The drug
Physicochemical properties of the drug
Total concentration of the drug in the body
2. The protein
Quantity of protein available for drug–protein binding
Quality or physicochemical nature of the protein
synthesized
3. The affinity between drug and protein
4. Drug interactions

17. Relationship between Protein
Concentration and Drug Concentration
in Drug–Protein Binding
• At low drug concentrations, most of the drug may be bound to
the protein, whereas at high drug concentrations, the protein-
binding sites may become saturated, with a consequent rapid
increase in the free drug concentrations