An understanding of the role of enzyme localization of the liver on metabolite kinetics: a computer simulation.

The metabolic sequence of drug, D, to its primary (MI) and terminal (MII) metabolites as mediated by enzymes A and B, respectively, was chosen to illustrate metabolizing activities among hepatocytes in different regions of the liver lobule. Six models of distributions of the hepatocellular activities (intrinsic clearances for A and B) were defined with respect to the flow path in liver, and the concentrations D, MI, and MII in the liver were simulated. The extent of sequential metabolism of the primary metabolite was compared for these six models of enzymic distributions. It was found that when the average hepatic intrinsic clearances of A and B were high (almost complete extraction of both drug and primary metabolite during their single passage through the liver), the distributions of A and B were not important determinants of metabolite kinetics. By contrast, when the average hepatic intrinsic clearances of A and B were both low, the distributions of A and B exerted profound effects on metabolite kinetics. The sensitivity to enzymic distribution in this region, however, was difficult to assess due to difficulties in detecting low levels of MI and MII. The effects of enzymic distributions on metabolite disposition would be better detected in compounds (drug and metabolite) with intermediate extraction ratios.