Protein binding refers to the ability of proteins to bond with other substances, such as drugs, in the bloodstream. The strength of the bond and the amount of drug bound determine its effectiveness. Proteins have binding sites that can fit other molecules, and the chemical properties of both are important for binding. The amount of bound and unbound drug is determined by their affinity for the protein and their relative concentrations. Renal insufficiency and liver disease can affect drug absorption, and testing can be done to determine the extent of binding.
Protein binding describes the ability of proteins to form bonds with other substances and most commonly refers to the binding of drugs to these molecules in blood plasma, red blood cells, other blood components and tissue membranes. It can, however, refer to other chemicals that enter the bloodstream. In the context of pharmacology, the amount of drug bound determines how effective it is in the body. The bound drug is kept in the bloodstream while the unbound component can 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 5% is active in the system and causing drug effects.
How does the bonding happen?
Proteins are very large and enormously complex molecules made up of chains of amino acids joined by peptide bonds and can take on a variety of complicated shapes. They can bind to molecules, including other proteins, in particular places known as binding sites, which often consist of indentations where other molecules, or parts of them, can fit snugly. The chemical properties of the binding site and the other molecule are also important: binding will only take place if chemically feasible. A single protein can have more than one binding site.
One example is hemoglobin, the protein responsible for carrying oxygen from the lungs to other parts of the body. It has four sites that can bind to an oxygen molecule. The bond formed in this case is rather weak – it has to be so that oxygen can be easily removed to where it is needed. In other cases, the molecules may bind more strongly. The tendency of a drug to bind to proteins and the strength of the binding are important factors in pharmacology.
Drug binding
Proteins commonly involved in drug binding are albumin, lipoproteins, and α1-acid glycoprotein (AGP). Acidic and neutral compounds will tend to bind with albumin, which is basic, while basic substances will bind primarily to the acidic AGP molecule. Acidic molecules can also bind to lipoproteins if albumin is saturated. This is not binding in the strict sense of the word; it is closest to dissolving and is common in lipid or fat soluble substances.
The bond is often reversible and in these cases can create a chemical equilibrium, where the chemical reaction can go back and forth without net changes in reactants and products. This is represented as:
protein + drug ⇌ protein-drug complex
If the concentration of unbound drug is reduced, part of the protein-drug complex can break down to release more compound, maintaining equilibrium. This means that a cell that is good at extracting unbound drug can extract more as the complex divides to restore balance.
The amount of bound and the unbound fraction—written as the amount of unbound drug out of the total amount—are determined by the compound’s affinity for the protein and their relative concentrations. This is important when considering other medications a patient may be taking. Some proteins may already be saturated, which would affect the amount of free drug and could change drug effects.
For example, if drug A saturates a certain binding protein and thus drug B is unable to bind to it, then there would be a higher concentration of unbound B. Alternatively, if drug B has a higher chemical affinity for the protein, it could displace A, elevating its unbound fraction. This process happens quite quickly, within minutes or hours, and both scenarios could have adverse effects. Many drugs, however, either bind to different proteins or to different sites on the protein, or are not present in a high enough relative concentration to cause saturation, and therefore do not compete with other drugs in use.
Likewise, the body’s ability to absorb a drug can affect its elimination from the system. Renal insufficiency and liver disease often adversely affect the ability to absorb unbound drug. For these reasons, consideration should be given to previous medical problems, the total concentration and unbound fraction of the drug, and any other medications a patient may be taking.
Testing
Newly developed drugs can be tested for their tendency to bind to proteins using a protein binding assay. This can be done with appropriate plasma or tissue samples, which can be incubated with the agent to be tested. After a certain period of time, the bound and unbound parts are separated, for example by using a very fine filter which does not allow the passage of large protein molecules, and the extent of the binding can then be determined.
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