DISTRIBUTION KINETICS OF SALICYLIC-ACID IN THE ISOLATED-PERFUSED RAT-LIVER ASSESSED USING MOMENT ANALYSIS AND THE 2-COMPARTMENT AXIAL-DISPERSION MODEL

The distribution kinetics of salicylic acid in the single-pass isolate d perfused rat liver has been investigated under varying conditions of perfusate flow (15 to 30 ml min(-1)) and of salicylate perfusate conc entration (0, 100, 200 mg l(-1))using statistical moment analysis and the two-compartment axial dispersion model. Salicylic acid was not met abolised during the experiment. The perfusate did not contain binding protein. As flow rate was increased, the maximum fraction output per s econd (f(t)(max)) increased and the mean transit time (MTT(H)) decreas ed, while t(max) became shorter for bath tritiated water and C-14-sali cylic acid. Increasing the salicylate perfusate concentration profound ly affected the frequency outflow profile of C-14-salicylic acid, but not that of tritiated water. The one-compartment axial dispersion mode l adequately described the frequency outflow profile for tritiated wat er, whereas the two-compartment form, which incorporates a cellular pe rmeability barrier, provided a better description of the C-14-salicyli c acid outflow data. The estimated two-compartment axial dispersion mo del parameters for C-14-salicylic acid, D-N, the dispersion number (0. 08 +/- 0.03), k(12), the influx rate constant (0.56 +/- 0.04 sec(-1)) and k(21), the efflux rate constant (0.095 +/- 0.01 sec(-1)) were inde pendent of perfusate flow rate. The in situ permeability-surface area product for C-14-salicylic acid (4.6 +/- 0.7 ml min(-1) g(-1) liver) w as in good agreement with literature estimates obtained from in vitro hepatocyte experiments, suggesting that the permeability barrier is at the hepatocyte membrane. Whereas D-N and k(12) were uninfluenced by, k(21) displayed a positive correlation with, salicylate perfusate conc entration. This correlation was most likely due to decreased intracell ular salicylate binding.