Volume of distribution in pharmacokinetics and clinical medicine: a critical update

The concept of pharmacokinetic volume of distribution (Vd) was first described > 90 years ago. Vd can provide a quantitative estimate of drug distribution to a hypothetical 'peripheral' space outside the blood or plasma (the measurement site), assuming concentration equality between blood and the peripheral space.

After single intravenous doses, calculation of Vd by the area method [Vd(area), also termed Vz or Vß] is the most stable and valid approach, since Vd(area) reflects drug distribution at all times after distribution equilibrium is attained, and depends only on observed properties of drug behaviour. In contrast, Vd by the steady-state method [Vd(ss)] is applicable only at a single time point, underestimates the actual extent of drug distribution, and is dependent on 'invisible' hypothetical rate constants. The notion that 'Vd(area) depends on elimination' is incorrect. Rather, Vd(area) and clearance-variables independent of each other-separately determine elimination half-life (T½), which is a dependent variable. T½ is an important property of drugs used in clinical practice, and can be altered-via changes in Vd(area) without changes in clearance-by factors such as obesity, age, and gender.

Vd (area) is the most appropriate metric reflecting in vivo drug distribution.