A Two-compartment Dispersion Model Describes the Hepatic Outflow Profile of Diclofenac in the Presence of its Binding Protein

Abstract

The residence-time distribution (RTD) of diclofenac in the rat single-pass isolated perfused in-situ liver (n = 4) was determined after bolus input into the hepatic portal vein. Addition of human serum albumin (5 g L-1) ensured extensive (greater than 98%) binding of diclofenac within the perfusate. The one-compartment form of the axial dispersion model of hepatic elimination, which assumes instantaneous radial distribution of substrate within the accessible spaces of the liver, failed to describe adequately the RTD of diclofenac. In contrast, the two-compartment form of this model, which assumes that the radial transfer of unbound substrate between the vascular and cellular space is non-instantaneous, provided an excellent description of the diclofenac data. Moreover, the mean (+/- s.d.) value for the hepatic dispersion number (DN) for diclofenac (0.354 +/- 0.076) compared well with that determined for simultaneously injected [125I]human serum albumin (0.456 +/- 0.078) using the one-compartment dispersion model. These estimates of DN, a stochastic parameter which characterizes the axial spreading of individual elements during transit through the liver, were similar in magnitude to those reported for other tracers in the rat perfused liver. The findings suggest that common factors influenced the RTD of diclofenac and its binding protein, and indicate that the two-compartment dispersion model may be a valuable tool for interpreting hepatic impulse-response data for solutes whose hepatic distribution and elimination is influenced by membrane permeability.