Kinetic studies on the intramolecular acyl migration of beta-1-O-acyl glucuronides: application to the glucuronides of (R)- and (S)-ketoprofen, (R)- and (S)-hydroxy-ketoprofen metabolites, and tolmetin by 1H-NMR spectroscopy.
Conjugation of carboxylate drugs with D-glucuronic acid is of considerable interest because of the inherent reactivity of the resulting beta-1-O-acyl glucuronides. These conjugates can degrade by spontaneous hydrolysis and internal acyl migration. beta-1-O-acyl glucuronides and their acyl migration products can also react covalently with macromolecules with potential toxicological consequences. The spontaneous degradation of the diastereoisomeric beta-1-O-acyl glucuronide metabolites of the racemic drug ketoprofen, two of its ring-hydroxylated metabolites and of tolmetin beta-1-O-acyl glucuronide was investigated by (1)H-NMR spectroscopy in buffer solutions, at pH 7.4 and 37 degrees C. A plot of the logarithm of the peak integrals against time revealed first-order kinetics. Degradation rates and half-lives were calculated for each glucuronide using first-order reaction equations. Tolmetin glucuronide had the fastest degradation rate, whilst all of the ketoprofen-related glucuronides had similar degradation rates. The degradation of the diastereoisomeric glucuronides was stereoselective, with the rate for the (S)-isomer always slower compared with the (R)-isomer by approximately a factor of 2.
Skordi
E
E
Biological Chemistry, Imperial College London, South Kensington, London, UK.
Wilson
I D
ID
Lindon
J C
JC
Nicholson
J K
JK
D002021:Buffers; D020723:Glucuronic Acid / Q000737:chemistry*; D007660:Ketoprofen / Q000031:analogs & derivatives* / Q000737:chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D013237:Stereoisomerism; D014046:Tolmetin / Q000031:analogs & derivatives* / Q000737:chemistry
D002021:Buffers; C056583:tolmetin glucuronide; C044223:ketoprofen glucuronide; D020723:Glucuronic Acid; D007660:Ketoprofen; D014046:Tolmetin