Protein Binding

The macromolecular protein building blocks present within the body possess a variety of chemical properties. Some contain highly charged regions, and others have tertiary structures that result in regions of significant hydrophobicity or hydrophilicity. Drug molecules that come into contact with these macromolecules may interact with specific regions, and in some cases, this may result in the drug molecule binding with the macromolecule for a considerable period of time, typically via ionic or hydrophobic associations. The interactions can happen in any tissue or compartment within the body, and for the time period that the drug molecule is associated with the macromolecule, it does not contribute to the diffusible concentration of drug molecules. This effectively reduces the concentration of "free" drug and can alter (or determine) the distribution pattern of the drug. While there is still a lack of complete understanding of tissue binding, binding affinities to proteins in the blood are well characterized for a number of drug compounds.

There are two primary proteins within the blood that are involved with most drug binding. They are albumin, which commonly interacts with drugs that have acid properties, and aj-acid glycoprotein (gp), which binds with a number of basic drug molecules. Some of the lipoproteins present in the blood also interact and bind with certain drug molecules. If a drug has a high binding affinity to one of the plasma proteins, it is likely that most of the drug will remain in the bloodstream rather than penetrate into the body tissues. In such a case, changes in the protein concentration in the blood, specifically a decrease in the concentration, may result in an overall increase in the free concentration of the drug, and more drug will be able to distribute outside of the bloodstream. This may lead to an increase in the pharmacologic effect or in the side effects of the drug. The significance of protein (or other macromolecule) binding cannot be disregarded when determining the distribution pattern of a particular drug substance. In particular, for drugs with significant plasma protein binding, further characterization of the distribution changes in conditions where plasma protein concentrations may be altered are needed to minimize the likelihood of toxic or subtherapeutic concentrations of the drug occurring.

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