Factors Affecting Protein-Drug Binding

Factors affecting protein-drug binding are categorised as follows:

Drug-Related Factors

i) Physicochemical characteristics of drug,

ii) Concentration of drug in body, and

iii) Affinity of a drug for a particular binding component.

Protein/Tissue Binding-Related Factors

i) Physicochemical properties of the protein or binding agent,

ii) Concentration of protein or binding agent, and

iii) Number of binding sites on binding agent.

Drug Interactions :

i) Competition between drugs for a binding site (displacement interactions),

ii) Competition between drugs and normal body constituents, and

iii) Allosteric changes in protein molecule.

Patient-Related Factors

i) Age,

ii) Intersubject variations, and

iii) Disease states.

The drug-related factors which affect protein binding are discussed below:

Physicochemical Characteristics of Drug: Protein binding directly depends on the lipophilicity of drug; therefore an increase in lipophilicity increases the extent of binding. Highly lipophilic drugs (e.g., thiopental) localise in adipose tissues, anionic or acidic drugs (e.g., penicillins and sulphonamides) bind to HAS, cationic or basic drugs (e.g., imipramine and alprenolol) bind to AAG, and the neutral or unionised drugs bind to lipoproteins.
Concentration of Drug in Body: The extent of protein-drug binding can change with the changes that occur in drug and protein concentration. The concentration of drugs that bind to HSA shows a very little influence as the therapeutic concentration of any drug is not sufficient to saturate it. But, the therapeutic concentration of lidocaine can saturate AAG with which it binds as the concentration of AAG is less than that of HSA in blood.
Drug-Protein/Tissue Affinity: The affinity of drug-protein/tissue binding varies according to the drug molecule. For example, lidocaine shows more affinity for AAG than for HAS; Digoxin has more affinity for proteins of cardiac muscles than those of skeletal muscles or plasma; Iophenoxic acid (a radio-opaque medium) has a great affinity for plasma proteins.

The protein/tissue binding-related factors affecting the protein-drug binding are discussed below:

Physicochemical Properties of Protein or Binding Agent: Lipophilic drugs mainly bind to lipoproteins and adipose tissues as they get easily dissolved in their lipid core. The presence of active anionic and cationic groups on the albumin molecules to bind a variety of drugs depends on the physiological $pH$ (pH of blood, plasma, ECF, etc.).
Concentration of Protein or Binding Agent: Among the plasma proteins, binding mainly occurs with albumin because its concentration is higher than other plasma proteins. During diseased states, the amount of several proteins and tissue components available for binding gets changed.
Number of Binding Sites on Binding Agent: Albumin has numerous binding sites as well as high capacity binding component as compared to other proteins. Many drugs are capable of binding at more than one site on albumin. For example, flucloxacillin, flurbiprofen, ketoprofen, tamoxifen, and dicoumarol bind to both primary and secondary sites on albumin.

Drug Interactions

Drug-drug interaction affect drug-protein binding in the following way:

Competition between Drugs for a Binding Site (Displacement Interactions): A competition occurs between two or more drugs for interacting with a binding site if the drugs can bind to the same site. If one drug (drug A) binds to a specific site, administration of the other drug (drug B) that has affinity for the same site causes dislocation or displacement of drug A from its binding site. This type of drug-drug interaction for the common binding site is known as displacement interaction.

In this interaction, drug A is called the displaced drug while the drug B is called the displacer. In displacement interactions, an unexpected rise is observed in free concentration of the displaced drug, which may increase clinical response or toxicity of the particular drug molecule. Displacement interaction can be affected by a drug metabolite also. The clinical importance of this type of interaction can be given as:

i) The displaced drug (e.g., warfarin) has a binding capacity of more than $95%$ , has a small volume of distribution $(<0.15 L/kg)$ , shows a rapid onset of therapeutic or adverse effects, and has a narrow therapeutic index.

ii) The displacer drug (e.g., phenylbutazone) has a high affinity degree because the drug to be displaced competes for the same binding site. The drug/protein concentration ratio is high $(>0.10)$ and shows a rapid and large increase in plasma drug concentration.

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