The four factors discussed above will jointly govern the extent to which drug moves out of blood into tissues. Below Figure summarizes the spectrum of possibilities. The figure represents drug concentration by the degree of shading. In (a), nearly all the drug is retained in the blood with very little moving out into the tissues. In (c), we see the opposite pattern, most of the drug having moved into the tissues. Part (b) represents a more balanced outcome.

The ‘Volume of distribution’ is the parameter used to describe the behaviour of a particular drug. A situation such as (a) is conveyed by a small volume of distribution and that in (c) by a large value. The volume of distribution is usually represented by the symbol ‘V’.

a9

The spectrum of possible patterns of distribution for a drug.

The generation of a numerical value for V is explained via below figure:

a10

Start with something simpler than the human body – a bottle. The bottle in above Figure has a volume of V litres and a dose (D mg) of drug is added and allowed to dissolve and disperse evenly throughout the volume. The resultant concentration (C; in mg/L) will be:

C = D/V             

In an alternative scenario, we might not know the volume of the bottle, but we could determine this by adding a known dose of drug, stirring and then removing a sample for analysis, to determine drug concentration. We then calculate the volume by re-arranging the previous formula:

V = D/C

We can perform a similar operation in a patient – inject a known dose of drug, remove a blood sample to determine drug concentration and finally obtain a volume by the same calculation. The value we would obtain by this calculation is the volume of distribution for the drug. A simple example is shown in below Figure. It doesn’t matter whether the dose (50mg) was delivered into a bottle or a patient or whether the resultant concentration (0.25 mg/L) describes a laboratory solution or a patient’s blood sample. Either way the relevant volume is 200 Litres.

a11

It was stated earlier that the intended physical meaning of the volume of distribution was that it should reflect the extent of drug distribution out of the blood into the tissues. Below Figure shows that V does indeed reflect that property.

– In (a) most of the drug stays in the blood, leaving a high blood concentration. When we calculate V = D/C we obtain a small volume. We thus achieve the relationship we wanted – a low tendency for drug to move from the blood into the tissues is associated with a small value for V. – In (b) more of the drug has moved from the blood – this leaves a lower concentration – the calculated value of V is greater.

– In (c) there is very extensive movement- little drug remains in the blood – calculated V is appropriately large, reflecting the degree of movement into the tissues.

a12

Table shows the average volume of distribution in a 70kg adult for a range of drugs which have been selected to illustrate the wide range of values that can arise.

a13

Table: Volumes of distribution of substances with widely varying characteristics.

The three substances with small volumes are retained in the blood for differing reasons. Adalimumab is a monoclonal antibody (a protein with a molecular weight well over 100,000) that is virtually restricted to the plasma compartment. Warfarin binds tightly to serum albumin which prevents it from distributing and gentamicin is a very water soluble antibiotic with limited distribution and very little penetration into cells.