Protein binding

Protein binding refers to the interaction of various substances (ligands) with proteins in the body. These interactions can significantly influence the pharmacokinetics and pharmacodynamics of drugs. The binding of drugs to plasma proteins such as albumin, α1-acid glycoprotein, and lipoproteins affects their distribution, free concentration, and elimination.

Photo by National Cancer Institute on Unsplash

1. Free vs. Bound Drug:

   • Free Drug: The portion of the drug that is not bound to plasma proteins and is pharmacologically active.
   • Bound Drug: The portion of the drug that is bound to plasma proteins and is pharmacologically inactive.

2. Binding Sites:

   • Drugs can bind to multiple sites on a protein, but albumin is the most common binding protein in the plasma.

3. Factors Affecting Protein Binding:

   • Drug concentration
   • Affinity of the drug for the binding site
   • Concentration of binding proteins
   • Presence of other drugs or endogenous substances competing for binding sites

Examples

1. Warfarin:

   • Highly bound to albumin (about 97-99%).
   • Only the unbound fraction is responsible for its anticoagulant effect.
   • Drugs like aspirin can displace warfarin from albumin, increasing the free fraction and potentially causing bleeding.

2. Phenytoin:

   • Approximately 90% bound to plasma proteins, primarily albumin.
   • In patients with hypoalbuminemia (e.g., due to liver disease), the free fraction of phenytoin increases, leading to toxicity.

3. Diazepam:

   • About 98% bound to plasma proteins.
   • Competes with other drugs for binding sites, which can affect its pharmacological activity.

Chemical Reactions Involved in Protein Binding

Protein binding involves a range of chemical interactions:

1. Hydrophobic Interactions:

   • Nonpolar molecules or regions of molecules can interact with the hydrophobic regions of proteins.
   • Example: Binding of many lipophilic drugs to albumin.

2. Electrostatic Interactions:

   • Ionic bonds between charged drug molecules and charged amino acid residues on proteins.
   • Example: The binding of acidic drugs to albumin, which has a net negative charge.

3. Hydrogen Bonding:

   • Formation of hydrogen bonds between polar drug molecules and amino acid residues.
   • Example: Binding of drugs with hydroxyl or amine groups to proteins.

4. Van der Waals Forces:

   • Weak interactions between molecules due to temporary dipoles.
   • Example: Binding of various drugs to the relatively hydrophobic pockets of albumin.

Chemical Reaction Example

Consider a simplified scenario involving the binding of a drug (D) to a protein (P):

$P+D\leftrightarrow PD$

• $P$: Protein (e.g., albumin)
• $D$: Drug (e.g., warfarin)
• $PD$: Protein-drug complex

The binding can be described by an equilibrium constant $K_d$ (dissociation constant):

$K_d=\frac{[P][D]}{[PD]}$

A lower $K_d$ value indicates a higher affinity between the protein and the drug.

Summary

Protein binding is a crucial factor in drug pharmacokinetics, influencing drug distribution, efficacy, and safety. Understanding the interactions and factors affecting protein binding helps in predicting drug behavior and potential drug interactions in clinical settings.