Is volume of distribution at steady state a meaningful kinetic variable?

Pharmacokinetic volumes of distribution (Vd) are commonly calculated either by the steady-state method (Vdss) or the area method (Vdarea). Vdss is traditionally perceived as the least biased and most reliable indicator of the extent of distribution, but Vdss in fact has far greater practical and theoretical limitation than does Vdarea. After single doses or multiple discrete doses of a drug, Vdarea correctly relates plasma concentration to amount of drug in the body at all times after distribution equilibrium is attained. Vdss, on the other hand, is a correct proportionality constant only during continuous intravenous infusion or at a single instant in time after discrete dosing. Furthermore, calculated values of Vdss are strongly dependent on the precise configuration of the initial distributional phase of the plasma concentration curve, which may be difficult or impossible to delineate because of variance arising from methodologic artefacts or unexplained causes. Such variance can lead to large nonphysiologic within- and between-individual variability in Vdss. Vdarea, on the other hand, is relatively independent or artefactual changes in the initial distribution profile. Finally, experimental observations indicate that elimination depends physiologically on distribution in the absence of changes in clearance, not the reverse. The relation of distribution and elimination holds whether the steady-state method or the area method is used to calculate Vd. Thus, Vdarea is a more reliable and generally valid descriptor of the extent of drug distribution than is Vdss.