Reaction of 1-O-acyl glucuronides with 4-(p-nitrobenzyl)pyridine.
In this investigation, 31 1-O-acyl glucuronides were synthesized and 25 of these were shown to react with 4-(p-nitrobenzyl)pyridine (NBP), a standard chemical nucleophil, on thin layer chromatography plates. A quantitative NBP assay was developed based on existing methods, and the rates of reaction of three acyl glucuronides, clofibric 1-O-acyl glucuronide, indomethacin 1-O-acyl glucuronide, and flufenamic 1-O-acyl glucuronide, were determined. These rates ranged from 0.436 min-1 to 1.08 min-1. Chlorambucil, a powerful alkylating agent, reacted with NBP 127 times faster than the most reactive of the three glucuronides assayed. The half-lives of these three 1-O-acyl glucuronides, determined at pH 2.0, 4.0, 6.0, 7.4, and 10.0 in aqueous phosphate solution, ranged from greater than 1000 hr at pH 2 to less than 1 min at pH 10.0. Determination of the rates of reaction of 1-O-acyl glucuronides with NBP and the rates of hydrolysis as a function of pH further characterize these compounds as activated phase II metabolites.
van Breemen
R B
RB
Fenselau
C C
CC
D000478:Alkylation; D055598:Chemical Phenomena; D002621:Chemistry; D002994:Clofibrate / Q000031:analogs & derivatives; D002995:Clofibric Acid; D005439:Flufenamic Acid; D005965:Glucuronates; D007213:Indomethacin; D011725:Pyridines
D005965:Glucuronates; D011725:Pyridines; C008633:4-(4-nitrobenzyl)pyridine; D002995:Clofibric Acid; D005439:Flufenamic Acid; D002994:Clofibrate; D007213:Indomethacin