%0 Journal Article %A Rui Li %A Emi Kimoto %A Mark Niosi %A David A. Tess %A Jian Lin %A Larry M. Tremaine %A Li Di %T A study on pharmacokinetics of bosentan with systems modeling, Part 2: prospectively predicting systemic and liver exposure in healthy subjects %D 2018 %R 10.1124/dmd.117.078808 %J Drug Metabolism and Disposition %P dmd.117.078808 %X Predicting human pharmacokinetics of novel compounds is a critical step in drug discovery and clinical study design, but continues to be a challenging task for hepatic transporter substrates, particularly in predicting their liver exposures. In this study, using bosentan as an example, we have prospectively predicted systemic exposure and (pseudo) steady state unbound liver-to-unbound plasma ratio (Kpuu) in healthy subjects using (1) a mechanistic approach solely based on in vitro hepatocyte assays, and (2) an approach based on hepatic process rates from monkey in vivo data but Michaelis-Menten constants from in vitro data. Both methods reasonably match the observed human systemic time course data, but the second method leads to a better prediction accuracy. In addition, the second method can predict a human Kpuu that is almost identical to the value deduced using clinical data. We also generated rat and monkey liver Kpuu in terminal studies. However, these directly measured animal values are different from the deduced human value. %U https://dmd.aspetjournals.org/content/dmd/early/2018/01/12/dmd.117.078808.full.pdf