Drug Distribution

By , BPharm

When a drug is absorbed and enters the systemic circulation, it is naturally distributed throughout the fluid and tissues in the body. Drug distribution is a subject that is covered in a branch of pharmacology called pharmacokinetics.

The drug distribution is usually varied, and depends on several factors such as:

  • Blood perfusion
  • Tissue binding (since drug binding is linked to the lipid content)
  • Regional pH
  • Cell membrane permeability

Additionally, the rate at which a drug enters into a tissue depends on:

  • the flow of blood to the tissue
  • the mass of the tissue
  • the barriers existing between the blood and the tissue

The drug will eventually reach a distribution equilibrium, when the rate of drug entry and exit between the blood and the tissue is equal. At this point, when equilibrium has been reached, the concentration of the drug in the tissues and extracellular fluids is reflected by the concentration of the drug in the blood plasma. However, drug distribution is a dynamic process, because it occurs simultaneously with other pharmacokinetic processes such as drug metabolism and excretion.

Water-soluble drugs remain in the blood, but fat-soluble drugs are concentrated in the fatty tissues.  

Volume of Distribution

The apparent volume of distribution (VD) is the volume of fluid in which the total drug dose would theoretically have to be diluted to produce the observed drug concentration in the blood plasma. It can be calculated as follows:

Apparent volume of distribution = amount of drug in body / drug concentration in plasma

It is a theoretical value that is not related to the actual body volume of the individual, but is a useful pharmacokinetic parameter that indicates the distribution of the drug in the body.

For example, a drug that easily distributes into the tissues of the body will have a lower concentration in the blood, and the VD will be high as a result. Conversely, drugs that tend to remain in the blood and do not distribute easily to the tissue will have a higher concentration in the blood and a lower VD.

Binding

The distribution of a drug in the body also depends on the extent to which the drug binds to proteins and tissues in the body. Only drugs that are unbound to proteins and other components in the blood are free to diffuse across the cell membranes into the tissues of the body.

The most important proteins in the blood that can affect the distribution of a drug include the plasma protein albumin, the alpha-1 acid glycoprotein, and lipoproteins. It is observed that albumin binds acidic drugs, in general, while more basic drugs bind to the lipoproteins and acid glycoprotein. Although proteins are the most common binding sites in the blood, there are other molecules in the blood to which a drug molecule may bind.

As only the unbound drug can be utilized in extravascular and tissue sites, it is important to establish or estimate the unbound drug fraction in the blood. The following equation is used for this:

Unbound fraction = unbound drug concentration in plasma / total drug concentration in plasma

When there is a high concentration of drug in the body, there is an upper limit that is reached with respect to the total amount of drug that can be bound to proteins. This is based on the number of saturable binding sites.

Pharmaceutical substances can accumulate in tissues of the body. They may then be slowly released into the circulation as the blood concentration of the drug decreases, leading to a prolongation of drug action.  Some drugs may show a similar accumulation within the body cells, being bound to intracellular proteins, phospholipids or even the DNA or RNA.

Blood-Brain Barrier

The distribution of pharmaceutical substances to the brain and central nervous system (CNS) is limited by the blood-brain barrier, which inhibits the entry of most foreign substances. Some drugs that are lipid-soluble are able to cross the blood-brain barrier, whereas polar compounds are not able to enter. Still other pharmaceutical substances may be able to penetrate the CNS via the brain capillaries and cerebrospinal fluid.

Reviewed by Dr Liji Thomas, MD.

References

Further Reading

Last Updated: Jun 23, 2016

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