Membrane permeability and lipophilicity in the isolated perfused rat liver: 5-Ethyl barbituric acid and other compounds

The distribution kinetics of 5-ethyl barbituric acid (EBA) has been examined in the rat liver. The isolated in situ liver (n = 4) was perfused at a constant rate (15.1 ± 0.2 ml/min, mean ± S.D.) with protein-free Krebs bicarbonate medium in a single-pass mode. [¹⁴C]Sucrose (extracellular reference) and [¹⁴C]EBA were injected separately as bolus doses into the portal vein. The outflow data were analyzed using the axial dispersion model. The one-compartment dispersion model adequately described the data for sucrose, with a dispersion number (D(N)) of 0.25 ± 0.04 and a volume of distribution (V(H)) of 0.14 ± 0.01 ml/g liver. The two-compartment dispersion model, which incorporates a cellular permeability barrier, provided a better description of the EBA outflow data. The estimated V(H), influx and efflux rate constants and permeability-surface area product (PS) for EBA were 0.37 ± 0.04 ml/g liver, 0.028 ± 0.004 sec^-1, 0.019 ± 0.001 sec^-1 and 3.4 ± 0.5 ml/min, respectively. Despite low hepatocyte membrane permeability, the D(N) value for EBA (0.28 ± 0.03) was not significantly different from that of sucrose, which supports the concept that dispersion of compounds in the liver is primarily determined by the heterogeneity of the hepatic microvasculature. The relationship between PS values in the perfused rat liver (either abstracted or taken from the literature data) and physicochemical properties for 17 compounds has been explored. There appears to be a continuous relationship between PS and logD, a measure of lipophilicity that takes into account the degree of ionization in the perfusate. The PS value for EBA is close to that expected based on its physicochemical properties.