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Volume of Distribution

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The distribution of many drugs can be limited by their physicochemical properties. These include their lipid solubility, their extent of ionization in a given compartment, and their ability to bind to plasma or tissue proteins. When considering the volume of distribution (Vd) of drugs, it is important to understand the relationship between the actual volume of distribution and the apparent volume of distribution.

The actual volume of distribution of a drug is the anatomical volume of the body that is readily accessible to the drug. For example, a compound which is restricted to the plasma, possibly because of very strong binding to serum albumin, will have a volume of distribution equal to plasma volume, or about 3 liters in a 70 kg man. A highly charged compound that is unable to enter cells will be restricted to the extracellular space, a volume of about 12 liters in a 70 kg man. A drug that is moderately non-polar and distributes readily throughout the total body water will have a volume of distribution equal to total body water, which is about 60% of total body weight, or 42 liters in a 70 kg man. .

Vd = 42 L

C ~ 0.83 mg / L

On the other hand, the APPARENT VOLUME OF DISTRIBUTION is a purely calculated value that can be experimentally or clinically measured, and it can be useful in practice for determining the amount of drug that must be administered in order to achieve a desired plasma concentration.

The apparent volume of distribution, Vd, is calculated based on the fact that plasma drug concentration (C), which can be measured, is equal to the dose administered (D) divided by the volume: C = D/Vd Rearranging this equation, Vd = D/C

C = 10 mg IV / 3 L

C = 10 mg IV / 42 L

Vd = 10 mg IV / 0.83 mg / L

Vd = 12 L

C ~ 3 mg / L

C ~ 0.24 mg / L

D = 10 mg IV

Vd = 12 L

Vd = 42 L

Vd = 10 mg IV / 3 mg / L

Vd = 10 mg IV / 0.24 mg / L

C = 10 mg IV / 12 L

Vd = 3 L

From looking at this equation, any drug distribution process that results in a high plasma concentration (C) will result in a small apparent Vd. Such processes include any that keep drug trapped in the plasma compartment (such as very strong binding to serum albumin), so that the measured C is high.

Therefore by knowing the drug dose and by measuring the plasma drug concentration, the apparent volume of distribution, Vd, can be calculated.

drag

Plasma

Concentration of drugin the blood

Conversely, any distribution process that leads to a low value of plasma C or plasma concentration will produce a high apparent Vd. These processes include drug sequestration from the plasma into lipid as a result of the drug being highly lipid soluble.

Concentration of drugin the plasma

Concentration of drugin the body

It is important to emphasize that although the apparent Vd is a mathematically useful and measurable parameter that can help determine drug dosing requirements, it does not necessarily provide any information on the actual anatomical locations of the drug in the body. For example, a highly lipophilic drug that is sequestered in fat will have an actual volume of distribution roughly equal to the volume of body fat, while its calculated apparent volume of distribution may be even greater than total body volume, because according to the above equation, plasma C will be very low because the drug that is in the body but concentrated in fat rather than in plasma.

intracellular fluid

tissue binding and adipose

plasma compartment

extracellular fluid

Drugs can potentially distribute to various compartments within the body:

solubility

tissue binding

Drug distribution can be limited due to their physiochemical properties. These include their lipid solubility, their extent of ionization in a given compartment and/or if they bind to plasma or tissue proteins. This is important because if a drug is limited to the plasma, it is unable to reach its potential target site, and if it is “bound” or held within “reservoirs” it will not distribute and reach its target site and this may mean that it is not “available” to be cleared from the body.

plasma proteinbinding

ionization

How drug properties and its interactions with proteins/molecules within the body alters Vd

ECF

bone and muscle

free drug

ISF

blood

drug is plasmaprotein bound

ICF

The Law of Mass Action controls the amount of drug that is available to distribute throughout the body. In the example of plasma protein binding, this means that a drug is at equilibrium between a portion that is bound to proteins and a portion which is not. As free drug distributes from the plasma, drug which was previously bound dissociates from protein and is now available to “distribute” from plasma compartment. This means that although a drug is plasma protein bound- it is not “unable” to leave the plasma compartment- it is related however to the rate of other “free drug” molecules leaving.

Drug distribution

Tissue binding

Lipid solubility

One of the most common proteins that drugs bind to within the general circulation is albumin. Drugs which are highly bound are too large to be distributed readily from the plasma compartment. Therefore the drug concentration in the plasma is high, and the volume of distribution is low- as the drug does not readily distribute to “other” compartment.A drug which has limited interactions with proteins in the blood compartment are more readily able to distribute out of this compartment. As such- the plasma concentration of this drug is considered low and the volume of distribution is large because the drug distributes to other compartments.Two more factors that can affect how readily a drug distributes throughout the body are how lipid soluble the drug is and whether it binds to tissue proteins. Both of these factors increase the drugs volume of distribution because the drug is NOT in the plasma or blood compartment.