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 ex amined in the rat liver. The isolated in situ liver (n = 4) was perfus ed at a constant rate (15.1 +/- 0.2 ml/min, mean +/- S.D.) with protei n-free Krebs bicarbonate medium in a single-pass mode. [C-14]Sucrose ( extracellular reference) and [C-14]EBA were injected separately as bol us doses into the portal vein. The outflow data were analyzed using th e axial dispersion model. The one-compartment dispersion model adequat ely 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 cel lular permeability barrier, provided a better description of the EBA o utflow data. The estimated V-H, influx and efflux rate constants and p ermeability-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 co mpounds in the liver is primarily determined by the heterogeneity of t he hepatic microvasculature. The relationship between PS values in the perfused rat liver (either abstracted or taken from the literature da ta) 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 ionizat ion in the perfusate. The PS value for EBA is close to that expected b ased on its physicochemical properties.