In this study, we compared the lipophilicity of 0-glucuronides and their aglycones. Distribution coefficients (log D ) and P values of neutral species (log P ) were determined by centrifugal partition chromatography (CPC) in octanol/buffer systems. Two-phase potentiometry was also used to measure the log P value of some lipophilic solutes. The experimentally determined global influence of glucuronidation on lipophilicity, obtained as the difference (decrement) log ~g l u c u r o n i d e ) -log I;aplycone), was found to be -1.30 + 0.16 (n = 4) for glucuronides of alcohols (methyl, menthyl, neomenthyl, and chloramphenicol 0-glucuronide). The mean decrement was -2.06 0.31 (n = 9) for glucuronides of phenols (phenyl, p-nitrophenyl, I-naphthyl, 6-bromo-2-naphthy1, 4-methylumbelliferyl. 3-coumariny1, phenolphthalein, 4'-benzophenonyl 0-glucuronide, and diflunisal phenolic glucuronide). For the acylglucuronide of diflunisal and its rearrangement isomers, the mean decrement was -1.80 + 0.08 ( n = 4; range -1.7 to ~ 1.9). Differences in through-bond proximity effects as parametrized in the CLOGP algorithm seem to account for much of this difference. Conformational factors may also play a role, although it appears modest and unassessable for the glucuronides investigated here. The results imply that in vivo glucuronidation should have a stronger influence on the excretion of phenols than on that of alcohols.
B. T. and P.-A. C.