Defining drug disposition determinants: a pharmacogenetic-pharmacokinetic strategy

In preclinical and early clinical drug development, information about the factors influencing drug disposition is used to predict drug interaction potential, estimate and understand population pharmacokinetic variability, and select doses for clinical trials. However, both in vitro drug metabolism studies and pharmacogenetic association studies on human pharmacokinetic parameters have focused on a limited subset of the proteins involved in drug disposition. Furthermore, there has been a one-way information flow, solely using results of in vitro studies to select candidate genes for pharmacogenetic studies. Here, we propose a two-way pharmacogenetic-pharmacokinetic strategy that exploits the dramatic recent expansion in knowledge of functional genetic variation in proteins that influence drug disposition, and discuss how it could improve drug development.