Use of the Øie-Tozer Model in Understanding Mechanisms and Determinants of Drug Distribution

Volume of distribution (VD) is a key pharmacokinetic property that together with clearance determines the half-life or residence time of drug in the body. It is commonly expressed as steady-state volume of distribution VD_ss with a physiological basis for its understanding developed by Øie and Tozer in 1979. The Øie-Tozer equation uses terms for plasma protein binding (f_up), tissue binding (f_ut), and the extravascular/intravascular ratio of albumin as well as constants for the volumes of plasma, extracellular fluid, and tissue. We explored this model using a data set of 553 drugs for which VD_ss and plasma protein binding were available in humans. Eighteen percent of cases (102 compounds) did not obey the Øie-Tozer model, with the rearranged equation giving an aberrant f_ut value (f_ut < 0 or f_ut > 1), in particular for compounds with VD_ss < 0.6 l/kg and f_up > 0.1. Further analysis of this group of compounds revealed patterns in physicochemical attributes with a high proportion exemplified by logP less than 0 (i.e., very hydrophilic), polar surface area >150 Ų, and a difference between logP and logD >2.5. In addition there was a high representation of certain drug classes including anti-infectives as well as neuromuscular blockers and contrast agents. The majority of compounds were also found to have literature evidence, implicating active transport processes in their disposition. This analysis provides some important insights for pharmacokinetic optimization in this particular chemical space, as well as in the application of the Øie-Tozer model for predicting volume of distribution in humans.