Availability predictions by hepatic elimination models for Michaelis-Menten kinetics

Abstract

Numerical methods have been used to compare the availability predictions of a number of hepatic elimination models when Michaelis-Menten kinetics is operative. Propranolol and galactose were used as model compounds. Lower availabilities were predicted by the dispersion model than by a segregated distribution model for both compounds. The differences in the predictions were most pronounced for models corresponding to a large variation in solute residence times in the liver. The predictions of the tank-in-series, dispersion model with mixed boundary conditions and dispersion model with Dankwerts boundary conditions were similar over all concentrations studied. Changes in blood flow and protein binding provided little discrimination between the model predictions. It is concluded that micromixing of blood between sinusoids and the anatomical sites of mixing are important determinants of availability when liver eliminating enzymes are partially saturated.