Kinetic studies on the intramolecular acyl migration of β-1-O-acyl glucuronides: Application to the glucuronides of ( R )- and ( S )-ketoprofen, ( R )- and ( S )-hydroxy-ketoprofen metabolites, and tolmetin by 1 H-NMR spectroscopy

Author: Skordi E.   Wilson I. D.   Lindon J. C.   Nicholson J. K.  

Publisher: Informa Healthcare

ISSN: 1366-5928

Source: Xenobiotica, Vol.35, Iss.7, 2005-07, pp. : 715-725

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Abstract

Conjugation of carboxylate drugs with D-glucuronic acid is of considerable interest because of the inherent reactivity of the resulting β-1-O-acyl glucuronides. These conjugates can degrade by spontaneous hydrolysis and internal acyl migration. β-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 β-1-O-acyl glucuronide metabolites of the racemic drug ketoprofen, two of its ring-hydroxylated metabolites and of tolmetin β-1-O-acyl glucuronide was investigated by 1 H-NMR spectroscopy in buffer solutions, at pH 7.4 and 37°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.

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