The plasma-protein binding (PPB) of drugs and endogenous substances is of great importance for their pharmacokinetics. The extent of PPB can be measured using cloned receptors to compare the affinity of a ligand to the receptor and its affinity in the blood. The PPB is highly dependent on the blood pH.
Plasma-protein binding is one of the most important pharmacokinetic parameters.
Plasma-protein binding is one of the most important pharmacokinetic parameters. It regulates the actual concentration of drug in plasma and so affects the pharmacodynamic response to a drug. It also influences the rate and extent of distribution of drugs in the body, their metabolism and excretion (pharmacokinetic processes).
The extent of plasma-protein binding is expressed as a percentage. If a drug is completely bound to protein it will have an extent of 100%. Thus if 10 mg of a drug is given intravenously to give a plasma concentration of 1 mg litre−1, only 10% will be available for distribution and metabolism.
The remainder will be bound to plasma proteins, but as this is an equilibrium process these proportions are constantly changing and so the amount of free drug will also change.
Bound drug may or may not be pharmacologically active. If it is, then the equilibrium between bound and unbound forms determines the activity at receptors. Conversely, if the bound form is inactive, then it cannot affect receptors even though it determines its own pharmacokinetics by affecting those of its unbound form.
Plasma-protein binding is one of the most important pharmacokinetic parameters. In many cases, it is not necessary to measure the concentrations of free drug in plasma because the plasma protein binding of a drug is constant and the drug concentration can be calculated directly from this value.
The following list presents some of the important points that are related to plasma protein binding:
- The fraction (proportion) of a drug that binds to proteins in plasma should be known.
- The physiologically active fraction (free fraction) of a drug will be displaced if another compound is present in plasma that shares its binding sites on plasma proteins.
- As blood flows through the capillaries, free drug passes out of the blood into the tissue fluid by diffusion. The amount of free drug available for diffusion into tissues is dependent on its plasma protein binding and its concentration in plasma.
- Drugs can compete for specific binding sites with each other or with endogenous substances such as bilirubin, thyroxine, and corticosteroids.
Plasma-protein binding is inversely related to the clearance of drugs.
Plasma-protein binding is inversely related to the clearance of drugs. This means that the less a drug binds to plasma proteins, the higher its clearance will be. The reason behind this finding is that drugs that are not bound to plasma proteins are free to be eliminated from the body more rapidly than those that are bound. Let’s take a closer look at how this works.
When a drug binds to plasma proteins, it can no longer freely move around in the bloodstream. Instead, it becomes trapped inside the plasma protein’s circulating complex and is unable to be eliminated by excretion organs such as the kidneys or liver.
Because plasma proteins have an extended half-life, this can significantly increase the overall time it takes for a drug to be eliminated from the body (compared with if it was not bound to plasma proteins).
In contrast, drugs that are not bound to plasma proteins are able to freely flow throughout the bloodstream and be eliminated more quickly by excretion organs such as kidneys or liver. As a result, drugs with high clearance rates tend to have low levels of plasma protein binding and vice versa.
When a drug is bound to a plasma protein, it is not free to be excreted from the body. The amount of unbound drug in the bloodstream determines how much can be removed from the body. Therefore, drugs which bind more tightly to plasma proteins will be cleared more slowly from the bloodstream and remain in the system for longer periods of time.
The volume of distribution, bioavailability and half-life are independentof plasma-protein binding.
Plasma-protein binding of a drug is a physical phenomenon, in which parts of the drug are bound to various plasma proteins, such as albumin.
This phenomenon has various effects on certain pharmacokinetic properties, which can be mostly attributed to the decrease in the free (unbound) drug concentration. These effects include decreased volume of distribution, decreased bioavailability and decreased half-life.
The protein binding of drugs in plasma has a significant influence on the volume of distribution and bioavailability of such drugs. The fraction of unbound drug is available for tissue distribution and therefore, the bound fraction does not contribute to the volume of distribution.
The fraction of unbound drug is also able to cross biological membranes and therefore, the bound fraction does not contribute to the bioavailability. However, the half-life of a drug is not affected by its plasma-protein binding because the bound drug is still metabolized at a constant rate.
Finally
Plasma protein binding results in a reduction in free concentration of drug in blood, which is an inverse function of the plasma protein concentration. Thus, considering that there is a direct relationship between free concentration of drug and its biological activity, it can be inferred from the above statement that plasma-protein binding increases with increasing drug concentration.