Mechanisms of Protein-Drug Binding

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Chapter: Biopharmaceutics and Pharmacokinetics : Protein Binding of Drugs

A drug in the body can interact with several tissue components of which the two major categories are 1. Blood, and 2. Extravascular tissues.


Protein Binding of Drugs

A drug in the body can interact with several tissue components of which the two major categories are –

1. Blood, and

2. Extravascular tissues.

The interacting molecules are generally the macromolecules such as proteins, DNA or adipose. The proteins are particularly responsible for such an interaction. The phenomenon of complex formation with proteins is called as protein binding of drugs.

Protein binding may be divided into –

1. Intracellular binding  where the drug is bound to a cell protein which may be the drug receptor; if so, binding elicits a pharmacological response. These receptors with which drug interact to show response are called as primary receptors.

2. Extracellular binding  where the drug binds to an extracellular protein but the binding does not usually elicit a pharmacological response. These receptors are called secondary or silent receptors.

The most important extracellular proteins or silent receptors are plasma proteins, in particular albumin. Binding to such proteins is important from the viewpoint that the bound drug is both pharmacokinetically as well as pharmacodynamically inert i.e. an extracellular protein bound drug is neither metabolised nor excreted nor it is active pharmacologically. A bound drug is also restricted since it remains confined to a particular tissue for which it has greater affinity. Moreover, such a bound drug, because of its enormous size, cannot undergo membrane transport and thus its half-life is increased.


Mechanisms of Protein-Drug Binding

Binding of drugs to proteins is generally reversible which suggests that it generally involves weak chemical bonds such as –

1. Hydrogen bonds

2. Hydrophobic bonds

3. Ionic bonds, or

4. van der Waal’s forces.

Irreversible drug binding, though rare, arises as a result of covalent binding and is often a reason for the carcinogenicity or tissue toxicity of the drug; for example, covalent binding of chloroform and paracetamol metabolites to liver results in hepatotoxicity.

Binding of drugs falls into 2 classes:

1. Binding of drugs to blood components like—

a. Plasma proteins

b. Blood cells

2. Binding of drugs to extravascular tissue proteins, fats, bones, etc.

The influence of binding on drug disposition and clinical response is shown in Fig. 4.1.


Fig. 4.1. Protein-drug binding: Binding of drugs to various tissue components and its influence on disposition and clinical response. Note that only the unbound drug moves reversibly between the compartments.

Of all types of binding, the plasma protein-drug binding is the most significant and most widely studied.

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