An integrated approach to model hepatic drug clearance.

It has been well accepted that hepatic drug extraction depends on the blood flow, vascular binding, transmembrane barriers, transporters, enzymes and cosubstrate and their zonal heterogeneity. Models of hepatic drug clearances have been appraised with respect to their utility in predicting drug removal by the liver. Among these models, the "well-stirred" model is the simplest since it assumes venous equilibration, with drug emerging from the outflow being in equilibrium with drug within the liver, and the concentration is the same throughout. The "parallel tube" and dispersion models, and distributed model of Goresky and co-workers have been used to account for the observed sinusoidal concentration gradient from the inlet and outlet. Departure from these models exists to include heterogeneity in flow, enzymes, and transporters. This article utilized the physiologically based pharmacokinetic (PBPK) liver model and its extension that include heterogeneity in enzymes and transporters to illustrate how in vitro uptake and metabolic data from zonal hepatocytes on transport and enzymes may be used to predict the kinetics of removal in the intact liver; binding data were also necessary. In doing so, an integrative platform was provided to examine determinants of hepatic drug clearance. We used enalapril and digoxin as examples, and described a simple liver PBPK model that included transmembrane transport and metabolism occurring behind the membrane, and a zonal model in which the PBPK model was expanded three sets of sub-compartments that are arranged sequentially to represent zones 1, 2, and 3 along the flow path. The latter model readily accommodated the heterogeneous distribution of hepatic enzymes and transporters. Transport and metabolic data, piecewise information that served as initial estimates, allowed for the unknown efflux and other intrinsic clearances to be estimated. The simple or zonal PBPK model provides predictive views on the hepatic removal of drugs and metabolites.