The ØieTozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior

Introduction: Drug distribution is a major pharmacokinetic process that affects the time course of drug concentrations in tissues, biological fluids and the resulting pharmacological activities. Drug distribution may follow different pathways and patterns, and is governed by the drug's physicochemical properties and the body's physiology. The classical ØieTozer model is frequently used for predicting volume of drug distribution and for pharmacokinetic calculations. Areas covered: In this review, the suitability of the ØieTozer model for drugs that exhibit different distribution patterns is critically analyzed and illustrated. The method used is a pharmacokinetic modeling and simulation approach. It is demonstrated that the major limitation of the ØieTozer model stems from its focus on the total drug concentrations and not on the active (unbound) concentrations. Moreover, the ØieTozer model may be inappropriate for drugs with nonlinear or complex pharmacokinetic behavior, such as biopharmaceuticals, drug conjugates or for drugs incorporated into drug delivery systems. Distribution mechanisms and alternative distribution models for these drugs are discussed. Expert opinion: The ØieTozer model can serve for predicting unbound volume of drug distribution for 'classical' small molecular mass drugs with linear pharmacokinetics. However, more detailed mechanism-based distribution models should be used in preclinical and clinical settings for drugs that exhibit more complex pharmacokinetic behavior.