Influence of albumin on the distribution and elimination kinetics of diclofenac in the isolated perfused rat liver: analysis by the impulse-response technique and the dispersion model

Abstract

The impulse-response technique was used to investigate the influence of changes in the perfusate concentration of human serum albumin (HSA; 1.5-25 g/L) on the distribution and elimination kinetics of [14C]diclofenac in the isolated perfused rat liver. Output data were analyzed by a linear systems approach in combination with the axial dispersion model of hepatic elimination. This stochastic model is characterized by a dimensionless parameter (the dispersion number, DN) that quantifies the relative spreading of a substance as it passes through the liver. The two-compartment form of the axial dispersion model, which assumes that the radial transfer of a substance between the vascular and cellular spaces proceeds at a finite rate, was used to describe the output profiles for diclofenac, thereby providing estimates for DN and the first-order rate constants for the transfer of drug between the vascular and cellular compartments (k12 and k21) and its sequestration from the cellular compartment (kel). With a change in perfusate HSA concentration, the only one of these parameters to alter significantly (analysis of variance, p < 0.05) was the uptake rate constant (k12), which increased from 0.091 +/- 0.016 (mean +/- standard deviation) to 0.79 +/- 0.09 s-1 as HSA decreased from 25 to 1.5 g/L. Most of this change could be accounted for by an increase in the fraction of diclofenac unbound in perfusate, from 0.0030 to 0.0407 as HSA decreased from 25 to 1.5 g/L.(ABSTRACT TRUNCATED AT 250 WORDS)