NMR spectroscopic studies of the transacylation reactivity of ibuprofen 1-β-O-acyl glucuronide

The products arising from the intra-molecular acyl migration reactions of drug ester glucuronides can be reactive towards cellular proteins and have been proposed to cause toxic side effects. The relative reactivity of a range of drug and model glucuronides have previously been determined by measuring the rate of disappearance of a peak characteristic of the 1-β-O-acyl glucuronide using 1H NMR spectroscopy. Here the degradation rate of ibuprofen 1-β-O-acyl glucuronide has been investigated using NMR spectroscopy for the first time using material isolated from human urine with solid-phase extraction chromatography (SPEC). The degradation rate was measured by following the disappearance of the 1H NMR signal from the 1-β-anomeric proton of the glucuronic acid moiety as the reaction progressed in pH 7.4 buffer inside an NMR tube. The measured degradation rate represents a pseudo-first order rate constant, a combination of the transacylation rate (1-β-isomer to 2-β-isomer) and the hydrolysis rate, and is presented as a half-life of 3.5 h. This value is compared to those from drug glucuronides where adverse effects have been observed in patients after administration of the drug.