INTRINSIC AND INTRAMOLECULAR LIPOPHILICITY EFFECTS IN O-GLUCURONIDES

In this study. we compared the lipophilicity of O-glucuronides and the ir aglycones. Distribution coefficients (log D) and P values of neutra l species (log P) were determined by centrifugal partition chromatogra phy (CPC) in octanol:buffer systems. Two-phase potentiometry was also used to measure the log P value of some lipophilic solutes. The experi mentally determined global influence of glucuronidation on lipophilici ty. obtained as the difference (decrement) log P-(glucuranide) - log P -(aglycone), was found to be - 1.30 +/- 0.16 (n = 4) for glucuronides of alcohols (methyl. menthyl, neomenthyl, and chloramphenicol O-glucur onide). The mean decrement was - 2.06 +/- 0.31 (n = 9) for glucuronide s of phenols (phenyl, p-nitrophenyl, 1-naphthyl, 6-bromo-2-naphthyl, 4 -methylumbelliferyl, 3-coumarinyl, phenolphthalein, 4-benzophenonyl O- glucuronide, and diflunisal phenolic glucuronide). For the acylglucuro nide of diflunisal and its rearrangement isomers, the mean decrement w as - 1.80 +/- 0.08 (n = 4; range - 1.7 to - 1.9). Differences in throu gh-bond proximity effects as parametrized in the CLOGP algorithm seem to account for much of this difference. Conformational factors may als o play a role, although it appears modest and unassessable for the glu curonides investigated here. The results imply that in vivo glucuronid ation should have a stronger influence on the excretion of phenols tha n on that of alcohols.