Protein binding of drugs

Plasma Protein Binding of drugs

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Plasma Protein Binding of drugs

Systemically administered drugs reach target organs and tissues through blood, which is a mixture of several substances, including proteins. In pharmacokinetic terms, the blood or the plasma is called the central compartment. In this compartment, drugs often bind plasma proteins. The drug exits the central compartment as it partitions into organs and tissues, called the peripheral compartment. Plasma protein binding of drugs is generally reversible, so that protein-bound drug molecules are released as the level of free drug in blood declines.

Plasma proteins involved

Blood plasma normally contains about 6.72 g of protein per 100 cm3, the protein comprising 4.0 g of albumin, 2.3 g globulin, and 0.24 g of fibrinogen. Albumin (commonly called human serum albumin [HSA]) is the most abundant protein in plasma and interstitial fluid. Plasma albumin is a globular protein consisting of a single polypeptide chain of molecular weight 67 kDa. It has an isoelectric point of 4.9 and, therefore, a net negative charge at pH 7.4. Nevertheless, albumin is amphoteric and capable of binding both acidic and basic drugs. Physiologically, it binds relatively insoluble endogenous compounds, including unesterified fatty acids, bilirubin, and bile acids.

Human serum albumin has two sites for drug binding:

  1. Site I (warfarin site) binds bilirubin, phenytoin, and warfarin.
  2. Site II (diazepam site) binds benzodiazepines, probenecid, and ibuprofen.

Plasma proteins other than albumin are sometimes the major binding partners of drugs. For example, dicoumarol is bound to β- and α-globulins, and certain steroid hormones are specifically and preferentially bound to particular globulin fractions. Among other proteins, α1-acid glycoprotein (AAG) binds to lipophilic cations, including promethazine, amitriptyline, and dipyridamole.

Factors affecting plasma-protein binding

The amount of a drug that is bound to plasma proteins depends on three factors:

  1. Concentration of free drug
  2. Drug’s affinity for the protein-binding sites
  3. Concentration of protein

Consequences of plasma-protein binding

The binding of drugs to plasma proteins can influence their action in a number of ways:

  1. Reduce free drug concentration. Protein binding affects antibiotic effectiveness, as only the free antibiotic has antibacterial activity. For example, penicillin and cephalosporins bind reversibly to albumin, thus affecting their free concentrations in plasma.
  1. Reduce drug diffusion. The bound drug assumes the diffusional and other transport characteristics of the protein molecules.
  1. Reduce volume of distribution. Only free drug is able to cross the pores of the capillary endothelium. Protein binding will affect drug transport into other tissues. When binding occurs with high affinity, the drug is preferentially localized in the plasma or the central compartment. In pharmacokinetic measurements, this reflects as a low volume of distribution of the drug.

However, some drugs (e.g., warfarin and tricyclic antidepressants) may exhibit both a high degree of PPP and a large volume of distribution. Although drug bound to plasma proteins is not able to cross biological membranes, binding of drugs to plasma proteins is in a dynamic equilibrium with the drug bound to plasma proteins.


If the unbound (or free) drug is able to cross biological membranes and has a greater affinity and capacity for binding to the tissue biomolecules, compared with the plasma proteins, the drug may exhibit high volume of distribution, despite also exhibiting high PPP.

As free drug moves across membranes and out of vascular space, the equilibrium shifts, drawing drug off the plasma protein to replenish the free drug lost from vascular space. This free drug is now also able to traverse membranes and leave vascular space. In this way, a drug with a very low free fraction (i.e., a high degree of PPP) can exhibit a large volume of distribution.

  1. Reduce elimination. Protein binding retards the metabolism and renal excretion of the drug. Proteins are not filtered through glomerular filtration. Thus, protein-bound drugs have reduced rate of filtration in the kidneys and metabolism in the liver.
  1. Increase risk of fluctuation in plasma free drug concentration.

Effect on dosing regimen

  • Lower metabolism and elimination of a plasma-protein-bound drug can lead to longer plasma half-life, compared with an unbound drug. Thus, the protein-bound drug may serve as a reservoir of drug within the body, maintaining free drug concentration through equilibrium dissociation process. This leads to long half-life and sustained plasma concentrations. Thus, dosing frequency would need to be adjusted in cases where drug’s PPP or the concentration of plasma proteins is affected (such as burns).
  • Dose adjustments are frequently required in the case of disease states that affect the protein to which the administered drug is bound. Certain disease states increase AAG concentration while reducing albumin concentration. For example, acute burns reduce the concentration of circulating albumin, resulting in an increase in the free fraction of drugs that are normally bound to albumin. On the other hand, AAG concentration is substantially increased after an acute burn, resulting in a decrease in the free fraction of drugs that are normally bound to this plasma protein.
  • Age-based dose adjustments often have to account for PPP of drugs. For example, newborns have selectively lower plasma protein levels than adults. Thus, although the neonatal HSA concentration at birth is 75%–80% of adult levels, AAG concentration is only ~50%. Thus, dose adjustment may be needed for drugs that bind AAG.
  • Drug–drug interactions. Drugs that compete for the same plasma- protein-binding site can displace one another. This can lead to increased free level of a drug. Minor perturbation in PPP can have a significant influence on free drug concentration. Thus, coadministration of certain drugs may be contraindicated or require dose adjustment.
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