Analysis of Nonlinear and Nonsteady State Hepatic Extraction with the Dispersion Model Using the Finite Difference Method

A numerical calculation method for dispersion models was developed to analyze nonlinear and nonsteady hepatic elimination of substances. The finite difference method (FDM), a standard numerical calculation technique, was utilized to solve nonlinear partial differential equations of the dispersion model. Using this method, flexible application of the dispersion model becomes possible, because (i) nonlinear kinetics can be incorporated anywhere, (ii) the input function can be altered arbitrarily, and (iii) the number of compartments can be increased as needed. This method was implemented in a multipurpose nonlinear least-squares fitting computer program, Napp (Numeric Analysis Program for Pharmacokinetics). We simulated dilution curves for several nonlinear two-compartment hepatic models in which the saturable process is assumed in transport or metabolism, and investigated whether they could definitely be discriminated from each other. Preliminary analysis of the rat liver perfusion data of a cyclic pentapeptide, BQ-123, was performed by this method to demonstrate its applicability.