Drug Distribution Part 2. Predicting Volume of Distribution from Plasma Protein Binding and Membrane Partitioning.

Abstract

Volume of distribution is an important pharmacokinetic parameter in the distribution and half-life of a drug. Protein binding and lipid partitioning together determine drug distribution. Here we present a simple relationship that estimates the volume of distribution with the fraction of drug unbound in both plasma and microsomes. Model equations are based upon a two-compartment system and the experimental fractions unbound in plasma and microsomes represent binding to plasma proteins and cellular lipids, respectively. The protein and lipid binding components were parameterized using a dataset containing human in vitro and in vivo parameters for 63 drugs. The resulting equation explains ~84% of the variance in the log of the volume of distribution with an average fold-error of 1.6, with 3 outliers. These results suggest that Vss can be predicted for most drugs from plasma protein binding and microsomal partitioning.