Assessment of the Kochak-Benet Equation for Hepatic Clearance for the Parallel-Tube Model: Relevance of Classic Clearance Concepts in PK and PBPK

This report reviews concepts related to operation of the classic parallel-tube model (PTM) for hepatic disposition and examines two recent proposals of a newly derived equation to describe hepatic clearance (CL_H). It is demonstrated that the proposed equation is identical to a re-arrangement of an earlier relationship from Pang and Rowland and provides a means of calculation of intrinsic clearance (CL_int,PTM) rather than CL_H as posed. We further demonstrate how classic hepatic clearance models with an assumed CL_int, while subject to numerous limitations, remain highly useful and necessary in both traditional pharmacokinetics (PK) and physiologically based pharmacokinetic (PBPK) modeling.