A commentary on “Are all measures of liver Kpuu a function of FH, as determined following oral dosing, or have we made a critical error in defining hepatic drug clearance?”

The clearance concept has been used in pharmacokinetics for over 50 years. However, there is still much debate regarding mathematical clearance models. A recent article discussed that there is a critical error in a basic assumption that leads to the mechanistic hepatic clearance models (Benet, L.Z., Sodhi, J.K., 2024. Are all measures of liver Kpuu a function of FH, as determined following oral dosing, or have we made a critical error in defining hepatic drug clearance? European Journal of Pharmaceutical Sciences 196, 106753. https://doi.org/10.1016/j.ejps.2024.106753). This commentary discusses this point based on the extended clearance model (ECM), which is increasingly used in modern drug discovery and development. Confusion about clearance can be avoided by using clearly defined drug concentrations based on hierarchical body structures.