It is rare in real life that a drug only divides over one volume. A drug is divided throughout the body and the volume of distribution depends upon where the drug distributes and where the concentration of the drug is measured. The concentration is most often measured in plasma, as this is the most accessible body fluid.
As a mathematical exercise, put 10 units of drug in, distributing over various tissues as seen in the Figure. Now we determine the volume of distribution of the drug. The concentration of drug in the plasma would be equal to 5 units/3 litres or 1.67 unit/litre. From this it follows that the Vd = Dose / concentration = 10 units / 1.67 units/litres = 6 litres.
See how drugs can distribute over different components and what this means in the human body by clicking here and selecting the body compartment model and the human body model (module 2 and 3).
Note that distribution of drug over different tissues can take time. If distribution is relatively slow, then the concentration in the plasma is relatively high, and often an increased elimination rate is observed until the distribution of the drug is settled.
Edoxaban and Apixaban are two Direct oral anticoagulants (DOACs). Edoxaban has a Vd around 1.5 L/kg, whereas Apixaban has a Vd of only 0.3 L/kg. This relatively large change in Vd between two drugs of the same class is not uncommon, and is related to the properties of the drug. Which of the following factors will likely NOT affect the distribution value of both drugs?
Extra info: Increasing the lipophilicity of the drug will most likely increase distribution to lipophilic tissues (thus increasing the volume of distribution). Increasing the molecular weight will less likely be transported over barriers (and thus reduce the volume of distribution). Reducing protein binding will increase the fraction of unbound drug that is able to be transported over barriers (thus increase the distribution). The dose is usually not affecting the distribution (unless saturation takes place).