What is the difference between bound and unbound drugs?

Answer 1

A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β' and γ globulins.

A drug in blood exists in two forms: bound and unbound. Depending on a specific drug's affinity for plasma protein, a proportion of the drug may become bound to plasma proteins, with the remainder being unbound. If the protein binding is reversible, then a chemical equilibrium will exist between the bound and unbound states, such that:Protein + drug ⇌ Protein-drug complex

Notably, it is the unbound fraction which exhibits pharmacologic effects. It is also the fraction that may be metabolized and/or excreted. For example, the "fraction bound" of theanticoagulant warfarin is 97%. This means that of the amount of warfarin in the blood, 97% is bound to plasma proteins. The remaining 3% (the fraction unbound) is the fraction that is actually active and may be excreted.

Protein binding can influence the drug's biological half-life in the body. The bound portion may act as a reservoir or depot from which the drug is slowly released as the unbound form. Since the unbound form is being metabolized and/or excreted from the body, the bound fraction will be released in order to maintain equilibrium.

Since albumin is basic, acidic and neutral drugs will primarily bind to albumin. If albumin becomes saturated, then these drugs will bind to lipoprotein. Basic drugs will bind to the acidicalpha-1 acid glycoprotein. This is significant because various medical conditions may affect the levels of albumin, alpha-1 acid glycoprotein, and lipoproteins.

Impact of the altered protein bindingOnly the unbound fraction of the drug undergoes metabolism in the liver and other tissues. As the drug dissociates from the protein more and more drug undergoes metabolism. Changes in the levels of free drug change the volume of distribution because free drug may distribute into the tissues leading to a decrease in plasma concentration profile. For the drugs which rapidly undergo metabolism, clearance is dependent on the hepatic blood flow. For drugs which slowly undergo metabolism, changes in the unbound fraction of the drug directly change the clearance of the drug.Note: The most commonly used methods for measuring drug concentration levels in the plasma measure bound as well as unbound fractions of the drug.

The fraction unbound can be altered by a number of variables, such as the concentration of drug in the body, the amount and quality of plasma protein, and other drugs that bind to plasma proteins. Higher drug concentrations would lead to a higher fraction unbound, because the plasma protein would be saturated with drug and any excess drug would be unbound. If the amount of plasma protein is decreased (such as in catabolism, malnutrition, liver disease, renal disease), there would also be a higher fraction unbound. Additionally, the quality of the plasma protein may affect how many drug-binding sites there are on the protein.

Drug interactionsUsing 2 drugs at the same time may affect each other's fraction unbound. For example, assume that Drug A and Drug B are both protein-bound drugs. If Drug A is given, it will bind to the plasma proteins in the blood. If Drug B is also given, it can displace Drug A from the protein, thereby increasing Drug A's fraction unbound. This may increase the effects of Drug A, since only the unbound fraction may exhibit activity. See the example below:Before DisplacementAfter Displacement% increase in unbound fractionDrug A% bound9590% unbound510+100Drug B% bound5045% unbound5055+10

Note that for Drug A, the % increase in unbound fraction is 100% -- hence, Drug A's pharmacologic effect has doubled. This change in pharmacologic effect could have adverse consequences.

This effect of protein binding is most significant with drugs that are highly protein-bound (>95%) and have a low therapeutic index, such as warfarin. A low therapeutic index indicates that there is a high risk of toxicity when using the drug. Since warfarin is an anticoagulant with a low therapeutic index, warfarin may cause bleeding if the correct degree of pharmacologic effect is not maintain