The effect of chemical modifications on octanol/water partition (log D) and permeabilities across Caco-2 monolayers

Abstract

In the past octanol/water partition coefficients (log D7.4) have been used extensively to predict intestinal absorption. More recently flux measurements across confluent monolayers of Caco-2 cells, a human colonic carcinoma cell line, have been introduced to estimate oral absorption. Recently we reported that dexamethasone-β-D-glucuronide (sodium salt) had a permeability coefficient that was one order of magnitude higher than dexamethasone-β-D-glucoside despite a two orders of magnitude lower log D7.4, i.e., the compound displaying the free acid moiety had a higher permeability than the uncharged dexamethasone-β-D-glucoside. This finding is inconsistent with the dogma that a higher log D7.4 should translate into a higher permeability coefficient. Therefore, the objective of the present study was to examine whether structures unrelated to steroids containing free acid moieties and their respective ethyl esters (uncharged) demonstrate similar characteristics. Using reversed-phase HPLC we have determined the octanol/water partition coefficient (log D7.4) and permeability coefficients across Caco-2 monolayers of a limited series of bioactive compounds based on a benzodiazepine-2,5-dione scaffold, displaying a free acid moiety and the respective ethyl ester. Our results indicate: i. ester prodrugs have approximately two orders of magnitude higher octanol/water partition coefficient (log D7.4) than the parents (free acids) and ii. the permeability coefficients of the prodrugs were lower than for the parents. We conclude log D7.4 may not be a good predictor of the permeability coefficient and oral absorption.