Taking into account drug concentration differences within the circulatory system, a unique definition of each of the basic pharmacokinetic parameters, clearance (CL), steady-state volume of distribution (Vss), and mean disposition residence time (MDRT), is given which is generally valid for linear systems. The conventional relationship MDRT = Vss/CL holds theoretically only in the case of right atrial sampling following bolus intravenous injection. The values based on blood drug concentration from a peripheral venous sampling site are influenced by the pharmacokinetic properties of the lungs and the sampling tissue. Practically, the pulmonary extraction ratio and the mean transit time through the sampling tissue may thereby be of particular importance. Thus the effect of the sampling site on the pharmacokinetic parameters estimated by standard (classical) methods is quantitatively explained.