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 analy ze nonlinear and nonsteady hepatic elimination of substances. The finite di fference method (FDM), a standard numerical calculation technique, was util ized to solve nonlinear partial differential equations of the dispersion mo del. Using this method, flexible application of the dispersion model become s possible, because (i) nonlinear kinetics can be incorporated anywhere, (i i) the input function can be altered arbitrarily, and (iii) the number of c ompartments can be increased as needed. This method was implemented in a mu ltipurpose nonlinear least-squares fitting computer program, Napp (Numeric Analysis Program for Pharmacokinetics). We simulated dilution curves for se veral nonlinear two-compartment hepatic models in which the saturable proce ss is assumed in transport or metabolism, and investigated whether they cou ld definitely be discriminated from each other. Preliminary analysis of the rat liver perfusion data of a cyclic pentapeptide. BQ-123, was performed b y this method to demonstrate its applicability.