Fractal structure of the liver: effect on drug elimination

Liver modeling in pharmacokinetics has been based on outflow curves of extracellular tracers obtained in single-pass perfused rat livers. These reference curves represent the hepatic transit time densities (TTD) of tracers. Since the fractal structure of the sinusoidal network implies a TTD with power-law tail, the question is whether the use of conventional empirical TTDs with exponential tail may lead to biased estimates of hepatic clearance. A simulation study using a novel TTD model that accounts for fractal heterogeneity of hepatic flow shows that the bias is less than about 5%. Using this approach to determine the influence of hepatic flow dispersion on drug extraction, only a minor effect was found. The results demonstrate that there is no need for specific fractal models of hepatic drug elimination.