A new model-independent physiological approach to study hepatic drug clearance and its applications.

After entering the liver a drug molecule is removed by two competitive processes: (a) blood flow to carry it away intact from liver and (b) elimination by hepatic enzyme(s). The relative magnitude of the overall force or efficiency of these two processes will statistically decide its probability for elimination, i.e., extraction ratio (E). Blood flow rate is chosen to represent the force due to blood flow, and the force due to hepatic elimination can then be simply calculated in terms of blood flow per unit time. Under linear conditions any changes in either force can be used to predict new E. Binding in blood, permeability across hepatocellular membrane and intrinsic enzyme activity will affect the hepatic elimination force. The approach employed has virtually made no prior assumptions regarding distribution profiles of drug, enzymes, sinusoids and intracellular bindings as well as drug permeability. Bioavailability predictions upon changes in hepatic flow or protein binding are consistent with most reported data. It can explain potential differences in the fate of drug pre-equilibrated or not pre-equilibrated with blood before entering the liver and also that of metabolite performed or not performed in liver. Importance of erythrocytes as potential elimination barriers in hepatic first-pass effect and existence of both transverse and longitudinal (not considered in previous hepatic models) drug concentration gradients in the liver are emphasized. Applications to studies of instantaneous, time-averaged, beta and intrinsic clearances, as well as hepatic transit time and nonlinear kinetics are discussed. The present simple dynamic approach can also successfully predict the quantitative correlation between renal clearance and changes in urine flow and/or pH for many drugs in humans and animals. Using steady-state input conditions the present derived equations can be obtained thus adding the mathematical validity of the approach.