Tissue-to-blood distribution coefficients in the rat: utility for estimation of the volume of distribution in man.

A compilation of rat tissue-to-blood partition coefficient data obtained both in vitro and in vivo in thirteen different tissues for a total of 309 different drugs is presented. An evaluation of the relationship between several fundamental physicochemical molecular descriptors and these distribution parameters was made. In addition, the ability to predict the Human Volume of distribution by regression analysis and by a Physiologically-based approach was also tested. Results have shown different trends between the drug classes and tissues, consistent with earlier described relationships between physicochemical properties and pharmacokinetic behavior. It was also possible to conclude for the acceptable ability to predict the volume of distribution in Humans by both regression and mechanistic approaches, which suggests that this type of data represents a convenient tool to describe the drug distribution on a new drug development context. These observations and analyses, along with the large database of rat tissue distribution data, should enable future efforts aimed toward developing a full in silico quantitative structure-pharmacokinetic relationships and improving our understanding of the correlations between fundamental chemical characteristics and drug distribution.