Critical analysis of the discrepancy between V β and V ss for drugs exhibiting different two‐compartment disposition profiles

It is well known that in the two‐compartment open body model the values of apparent volume of distribution ( V β ) and volume of distribution at steady state ( V ss ) are never identical. There are at least two conditions when V β significantly overestimates V ss . The first is when most of a drug is eliminated relatively rapidly but a small fraction of the dose persists and gives rise to an extremely long half‐life. The second is when a drug is rapidly cleared from the central compartment with a short half‐life. The primary purpose of the current paper was to investigate how different two‐compartment disposition profiles affect the magnitude of difference between V β and V ss . Novel equations have been developed that relate the V β / V ss ratio to f 1 (fraction of drug elimination associated with the distributive phase) and to β/α (ratio of the exponential coefficients). This paper demonstrates mathematically that an increasing value of f 1 is associated with a greater divergence between V β and V ss . A similar relationship was also found for the divergence between the terminal half‐life ( t 1/2 β ) and the mean residence time ( MRT ). An increase in the β/α ratio results in a substantial decrease of this discrepancy and provides a maximal possible value, or an upper limit to the V β / V ss ratio. The newly derived equations along with their graphical presentation may serve as an excellent predictive tool for checking the accuracy of the experimentally obtained values of V β and V ss . Copyright © 2004 John Wiley & Sons, Ltd.