PHYSIOLOGICAL MODELS OF HEPATIC DRUG CLEARANCE - INFLUENCE OF ALTEREDPROTEIN-BINDING ON THE ELIMINATION OF DICLOFENAC IN THE ISOLATED-PERFUSED RAT-LIVER

The single-pass perfused rat liver preparation was used to assess the influence of binding to human serum albumin on the steady-state hepati c extraction of diclofenac (n = 8). In the absence of binding protein, the extraction ratio of diclofenac approached unity (range, 0.975-0.9 92), such that its clearance was perfusion-rate limited. As the bindin g of diclofenac to protein was increased by the addition of human seru m albumin to the perfusion medium, its extraction ratio decreased dram atically, and clearance eventually became capacity limited. The relati onship between diclofenac availability and fraction unbound was analyz ed with various physiologic models of hepatic drug clearance. The disp ersion model, which contains a parameter (the dispersion number) that quantifies the axial spreading of a substrate as it passes along the l iver length, provided a significantly better description of the data ( p < 0.05) than the undistributed parallel-tube model, which assumes th at an eliminated substrate travels through the liver as an undispersed plug, and the well stirred (venous equilibrium) model, which assumes that substrate undergoes infinite mixing as soon as it enters the live r. The dispersion number estimated for diclofenac (mean, 3.03; range, 0.89-7.56) was significantly greater than that predicted from consider ations of the transverse heterogeneity of blood flow within the hepati c sinusoidal bed, suggesting that additional factors influenced the re lationship between availability and fraction unbound for this compound . Such factors may include transverse heterogeneity of the metabolizin g enzyme system(s), axial flux of substrate created by diffusion withi n hepatic tissue, and protein-facilitated transfer of substrate across an unstirred fluid layer adjacent to the hepatocyte surface.