Abstract

There is overwhelming preference for application of the unphysiologic, well-stirred model (WSM) over the parallel tube model (PTM) and dispersion model (DM) to predict hepatic drug clearance, CL_H, despite that liver blood flow is dispersive and closer to the DM in nature. The reasoning is the ease in computation relating the hepatic intrinsic clearance (CL_int), hepatic blood flow (Q_H), unbound fraction in blood (fu_b) and the transmembrane clearances (CL_in and CL_ef) to CL_H for the WSM. However, the WSM, being the least efficient liver model, predicts a lower E_H that is associated with the in vitro CL_int (V_max/K_m), therefore requiring scale-up to predict CL_H in vivo. By contrast, the miniPTM, a three-subcompartment tank-in-series model of uniform enzymes, closely mimics the DM and yielded similar patterns for CL_int versus E_H, substrate concentration [S], and K_L/B, the tissue to outflow blood concentration ratio. We placed these liver models nested within physiologically based pharmacokinetic models to describe the kinetics of the flow-limited, phenolic substrate, harmol, using the WSM (single compartment) and the miniPTM and zonal liver models (ZLMs) of evenly and unevenly distributed glucuronidation and sulfation activities, respectively, to predict CL_H. For the same, given CL_int (V_max and K_m), the WSM again furnished the lowest extraction ratio (E_H,WSM = 0.5) compared with the miniPTM and ZLM (>0.68). Values of E_H,WSM were elevated to those for E_H,PTM and E_H,ZLM when the V_maxs for sulfation and glucuronidation were raised 5.7- to 1.15-fold. The miniPTM is easily manageable mathematically and should be the new normal for liver/physiologic modeling.