Quantitative evaluation of capacity-limited hepatobiliary transport based on hepatocellular diffusion model by...

The dose-dependency of hepatic uptake and hepatobiliary transport of a drug was evaluated by means of a nonlinear least square program incorporating the finite element method, MULTI(FEM). A perfusion experiment using isolated rat livers following a pulse input (i.e., under nonsteady-state conditions) was performed at three dose levels of cefpiramide as a model drug. The hepatic extraction ratio (E(H)) of cefpiramide decreased with an increase in dose, which demonstrates that the hepatic uptake is capacity-limited. The outflow time-profiles from the liver were represented by a two-compartment dispersion model with central Michaelis-Menten elimination, and the maximal elimination rate per central compartment volume (Vmax) and the Michaelis constant (Km) were estimated to be 1420 microg/ml/min and 235 microg/ml, respectively. The biliary mean transit time (t(bile)) increased slightly with an increase in dose. The hepatocellular diffusion model under non-steady-state conditions considering nonlinear transport across the bile canalicular membrane was adopted to evaluate dose-dependency in the biliary excretion of cefpiramide. The maximal penetration velocity across the bile canalicular membrane per liver (V=(bcm)max) and the affinity constant of penetration across the bile canalicular membrane (k(bcm)m = K(bcm)m A(H)L) were estimated to be 40.1 microg/min and 123 microg, respectively. Considering that the volume of a rat liver (A(H)L) is approximately 10 ml, the Michaelis constant of penetration (K(bcm)m), which is an apparent parameter, was estimated to be approximately 12.3 microg/ml. In conclusion, MULTI(FEM) is useful for evaluation of capacity-limited local disposition.