Application of a non-linear dispersion model to analysis of the renal handling of p-aminohippurate in isolated perfused rat kidney.

Abstract

To analyze the renal handling of therapeutic compounds observed as a non-linear process with a diffusion phenomenon, we employed a non-linear dispersion model described with a partial differential equation and solved it by using the finite difference method with an implicit scheme in a model dependent analysis. In this study, the renal handling of p-aminohippurate (PAH) was investigated in isolated perfused rat kidney, in which a 50 microl bolus of injection solution containing [3H]PAH and [14C]inulin was administered rapidly into the renal artery. The venous outflows were then collected for 15 min with a fraction collector. The renal extraction ratio of PAH was decreased from 65% to 18% as the PAH concentration in the injection solution was increased from 2 microM to 10 mM. The PAH outflow profile changed as the extraction process became saturated. With the non-linear dispersion model, the Michaelis-Menten parameters for the PAH extraction process were estimated by a model fitting calculation. The calculated values were 0.83 micromol/min/kidney for Vmax and 89 microM for Km. It was demonstrated that the model dependent analysis with a non-linear dispersion model is a useful approach to characterize renal drug handling, and is probably applicable for examining other non-linear processes which involve a diffusion phenomenon.