NMR spectroscopic studies of the transacylation reactivity of ibuprofen 1-beta-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-beta-O-acyl glucuronide using 1H NMR spectroscopy. Here the degradation rate of ibuprofen 1-beta-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-beta-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-beta-isomer to 2-beta-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.
Biological Chemistry, Biomedical Sciences Division, Sir Alexander Fleming Building, Imperial College, South Kensington, London SW7 2AZ, UK.
Stephen J
SJ
Vanderhoeven
John C
JC
Lindon
Jeff
J
Troke
Jeremy K
JK
Nicholson
Ian D
ID
Wilson
D000215:Acylation; D005965:Glucuronates / Q000737:chemistry*; D006868:Hydrolysis; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*
D005965:Glucuronates; C081281:ibuprofen acyl glucuronide; D007052:Ibuprofen