A simulation study on the effect of a uniform diffusional barrier across hepatocytes on drug metabolism by evenly or unevenly distributed uni-enzyme in the liver.

The effect of a uniform diffusional barrier on hepatic extraction of the parent drug by evenly or unevenly distributed uni-enzyme was quantitatively determined by the present simulation study. Five models of enzymic distribution were defined with regard to the hepatic blood flow path, and the extraction ratios were calculated or simulated under the various conditions of average intrinsic clearances and diffusion clearances across hepatocytes. Differences in the extraction ratios among the five models were evaluated by the "relative extraction ratios," which are the extraction ratios in each model divided by that in the model where the enzymatic activity is evenly distributed. It was found that when a diffusion clearance was high compared to the intrinsic clearance, enzymic distribution was not an important determinant of the extent of hepatic extraction. By contrast, when a diffusional barrier across hepatocytes exists, i.e., the diffusion clearance is low or intermediate compared to the intrinsic clearance, extraction ratios differed widely among the models of enzymic distribution, especially at intermediate average intrinsic clearances. In the presence of a diffusional barrier, the more skewed the distribution of the enzymatic activity is, the lesser the amount of drug eliminated at steady state. The most efficient metabolism occurred when the enzymatic activity was evenly distributed.