Assessing Liver-to-Plasma Partition Coefficients and In Silico Calculation Methods: When Does the Hepatic Model Matter in PBPK?

The primary models used in pharmacokinetics to assess hepatic clearance (CL_h) are the well-stirred model (WSM), the parallel tube model (PTM), and the dispersion model (DM) that differ in their internal flow patterns and assumed unbound liver concentrations. Physiologically based pharmacokinetic (PBPK) models require a hepatic intrinsic clearance (CL_int) and tissue-to-plasma partition coefficient (K_p). Given measured systemic and liver concentration-time profiles, these hepatic models perform similarly but yield model-specific CL_int and K_p estimates. This work provides mathematical relationships for the three basic hepatic models and assesses their corresponding PBPK-relevant K_p values with literature-reported single-dose blood and liver concentration-time data of 14 compounds. Model fittings were performed with an open-loop approach where the CL_h and extraction ratio (ER) were first estimated from fitting the blood data yielding CL_int values for the three hepatic models. The prefitted blood data served as forcing input functions to obtain PBPK-operative K_p estimates that were compared with those obtained by the tissue/plasma area ratio (AR), the Chen and Gross (C&G) method, and published in silico methods. The CL_int and K_p values for the hepatic models increased with the ER and both showed a rank order being WSM > DM > PTM. Drugs with low ER showed no differences as expected. With model-specific CL_int and K_p values, all hepatic models predict the same steady-state K_p that is comparable to those from the AR and C&G methods and reported by direct measurement. All in silico methods performed poorly for most compounds. Hepatic model selection requires cautious application and interpretation in PBPK modeling.