Based on the compartment- and model-independent or physiologically based clearance approaches, general equations to calculate the apparent steady-state volume of distribution of compounds (Vdss) are derived. The results show that either arterial plasma level data or the combination of venous plasma level data and cumulative urinary excretion data after a bolus or intravenous infusion can be used to calculate the Vdss. In view of the potential marked arterial-venous plasma concentration difference, and of the fact that the driving force for elimination and distribution should generally be the drug concentration in the arterial plasma use of venous data to calculate the Vdss as is commonly performed is inappropriate.