Mechanistic approaches to volume of distribution predictions: understanding the processes.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Rodgers
Trudy
T
Centre for Applied Pharmacokinetic Research, School of Pharmacy, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. trudy.rodgers@manchester.ac.uk
Rowland
Malcolm
M
D000465:Algorithms; D000818:Animals; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013678:Technology, Pharmaceutical / Q000379:methods; D014018:Tissue Distribution
D004364:Pharmaceutical Preparations