Structure-hepatic disposition relationships for phenolic compounds.

Phenolic compounds are widely used in therapeutic, environmental, and industrial applications. The present work seeks to define the hepatic disposition of 11 phenolic compounds with varying lipophilicities and molecular weights. The hepatic disposition kinetics were studied in a once-through in situ rat liver perfusion preparation in order to avoid extra-hepatic metabolism and recirculation effects. The phenols were administered using the impulse-response technique and the time course of hepatic venous effluent concentration was examined by moments and a two-compartment dispersion model. While the extraction of the phenolic compounds was relatively independent of lipophilicity, the estimated permeability-surface area (PS) product for influx of solutes into the hepatocytes could be related to the compounds' octanol-buffer partition coefficients (log Papp). This log PS-logPapp relationship was consistent with that reported earlier for another series of solutes with a wide range of lipophilicity. The metabolites produced from each of the phenolic compounds used in this study had mean transit times similar to those of their corresponding parent phenols, suggesting that the metabolites were not trapped in the liver as a consequence of their higher polarity. It is concluded that the strong solute lipophilicity-toxicity and lipophilicity-skin penetration relationships often seen for aqueous solutions of phenols are not evident for the hepatic extraction of these compounds. Such a conclusion is consistent with the hepatic extraction of phenolic compounds being mainly determined by a blood flow limitation in delivery of the phenol to the liver, rather than the intrinsic liver metabolic enzyme activities at the doses injected.