Plasma protein binding
Encyclopedia
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 globulin
s.
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:
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 the anticoagulant
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 acidic alpha-1 acid glycoprotein
. This is significant because various medical conditions may affect the levels of albumin, alpha-1 acid glycoprotein, and lipoproteins.
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.
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.
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 maintained. If a patient on warfarin takes another drug that displaces warfarin from plasma protein, such as a sulfonamide antibiotic, it could result in an increased risk of bleeding.
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
. 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
Human serum albumin
Human serum albumin is the most abundant protein in human blood plasma. It is produced in the liver. Albumin constitutes about half of the blood serum protein...
, lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
, glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
, α, β‚ and γ globulin
Globulin
Globulin is one of the three types of serum proteins, the others being albumin and fibrinogen. Some globulins are produced in the liver, while others are made by the immune system. The term globulin encompasses a heterogeneous group of proteins with typical high molecular weight, and both...
s.
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
Chemical equilibrium
In a chemical reaction, chemical equilibrium is the state in which the concentrations of the reactants and products have not yet changed with time. It occurs only in reversible reactions, and not in irreversible reactions. Usually, this state results when the forward reaction proceeds at the same...
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 the anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
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
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
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
Human serum albumin
Human serum albumin is the most abundant protein in human blood plasma. It is produced in the liver. Albumin constitutes about half of the blood serum protein...
. If albumin becomes saturated, then these drugs will bind to lipoprotein. Basic drugs will bind to the acidic alpha-1 acid glycoprotein
Orosomucoid
Orosomucoid or alpha-1-acid glycoprotein is an acute phase plasma alpha-globulin glycoprotein and is modulated by two polymorphic genes. It is synthesized primarily in hepatocytes and has a normal plasma concentration between 0.6-1.2 mg/mL...
. This is significant because various medical conditions may affect the levels of albumin, alpha-1 acid glycoprotein, and lipoproteins.
Impact of the altered protein binding
Only 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, clearanceClearance (medicine)
In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...
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
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
, malnutrition
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....
, liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
, 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 interactions
Using 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 Displacement | After Displacement | % increase in unbound fraction | |
|---|---|---|---|
| Drug A | |||
| % bound | 95 | 90 | |
| % unbound | 5 | 10 | +100 |
| Drug B | |||
| % bound | 50 | 45 | |
| % unbound | 50 | 55 | +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
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
, 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 maintained. If a patient on warfarin takes another drug that displaces warfarin from plasma protein, such as a sulfonamide antibiotic, it could result in an increased risk of bleeding.