Effect of diffusional barriers on drug and metabolite kinetics

Previous experimental and simulation studies have alluded to the presence of a diffusional barrier for enalaprilat, the polar, dicarboxylic acid metabolite of enalapril, entering hepatocytes. The present study examined the roles of diffusional clearances of drug and metabolite on the distribution and elimination characteristics in liver. The hepatic intrinsic clearances for enalapril (26.1 ml/min) and enalaprilat (0.7 ml/min), found in a previous study, were used for simulation because, along with their given diffusional clearances (75 and 2 ml/min, respectively), they yielded a high extraction ratio for drug (E = 0.86) and a poor extraction ratio for the preformed metabolite (E = 0.05). While maintaining the intrinsic clearances and hepatic blood flow rate (10 ml/min) constant, only drug and metabolite diffusional clearances were altered. The liver was modeled as three (blood, liver tissue, and bile) compartments, with blood flowing into sinusoids of uniform length L. Blood (sinusoidal) and tissue concentrations of drug and generated and preformed metabolites, at any point x along L and under linear kinetic conditions, were approximated numerically by computer simulations and expressed as the length-averaged or mean concentrations. The factors underlying drug and metabolite (preformed and generated) concentrations, hepatic clearances and elimination rates, and their interrelationships were illustrated graphically, emphasizing the roles of diffusional clearances for drug and metabolite on their spatial distributions and elimination in liver.