Distribution kinetics of salicylic acid in the isolated perfused rat liver assessed using moment analysis and the two-compartment axial dispersion model.

Abstract

The distribution kinetics of salicylic acid in the single-pass isolated perfused rat liver has been investigated under varying conditions of perfusate flow (15 to 30 ml min-1) and of salicylate perfusate concentration (0, 100, 200 mg l-1) using statistical moment analysis and the two-compartment axial dispersion model. Salicylic acid was not metabolised during the experiment. The perfusate did not contain binding protein. As flow rate was increased, the maximum fraction output per second (f(t)max) increased and the mean transit time (MTTH) decreased, while tmax became shorter for both tritiated water and 14C-salicylic acid. Increasing the salicylate perfusate concentration profoundly affected the frequency outflow profile of 14C-salicylic acid, but not that of tritiated water. The one-compartment axial dispersion model adequately described the frequency outflow profile for tritiated water, whereas the two-compartment form, which incorporates a cellular permeability barrier, provided a better description of the 14C-salicylic acid outflow data. The estimated two-compartment axial dispersion model parameters for 14C-salicylic acid, DN, the dispersion number (0.08 +/- 0.03), k12, the influx rate constant (0.56 +/- 0.04 sec-1) and k21, the efflux rate constant (0.095 +/- 0.01 sec-1) were independent of perfusate flow rate. The in situ permeability-surface area product for 14C-salicylic acid (4.6 +/- 0.7 ml min-1g-1 liver) was in good agreement with literature estimates obtained from in vitro hepatocyte experiments, suggesting that the permeability barrier is at the hepatocyte membrane. Whereas DN and k12 were uninfluenced by, k21 displayed a positive correlation with, salicylate perfusate concentration. This correlation was most likely due to decreased intracellular salicylate binding.