Mechanistic approaches to volume of distribution predictions: Understanding the processes

Purpose. To use recently developed mechanistic equations to predict tissue-to-plasma water partition coefficients (Kpus), apply these predictions to whole body unbound volume of distribution at steady state (Vu(ss)) determinations, and explain the differences in the extent of drug distribution both within and across the various compound classes. Materials and Methods. Vu(ss) values were predicted for 92 structurally diverse compounds in rats and 140 in humans by two approaches. The first approach incorporated Kpu values predicted for 13 tissues whereas the second was restricted to muscle. Results. The prediction accuracy was good for both approaches in rats and humans, with 64-78% and 82-92% of the predicted Vu(ss) values agreeing with in vivo data to within factors of +/- 2 and 3, respectively. Conclusion. Generic distribution processes were identified as lipid partitioning and dissolution where the former is higher for lipophilic unionised drugs. In addition, electrostatic interactions with acidic phospholipids can predominate for ionised bases when affinities (reflected by binding to constituents within blood) are high. For acidic drugs albumin binding dominates when plasma protein binding is high. This ability to explain drug distribution and link it to physicochemical properties can help guide the compound selection process.