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 by¹H-NMR spectroscopy

Abstract

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.

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

“…After administration of racemic ibuprofen it has been reported that the drug excreted in human urine is largely in the (S)-form, due to chiral inversion in vivo. If both R-and S-ibuprofen glucuronides had been present in the sample (as a diastereoisomeric mixture) [14] a pair of doublets would have been observed for the anomeric proton resonances, since these are clearly resolvable although there is some overlap of the J-coupled multiplets as shown by previous work on the chemically-related flurbiprofen [16] and ketoprofen [17]. However, from the measurements made here, the resonance observed for the anomeric proton showed only a single doublet.…”

“…Nevertheless, even in the absence of a large database of drug glucuronide half-life data, the half-life of 3.5 h determined here for ibuprofen glucuronide can also be compared with the value of 0.44 h for tolmetin [17] a drug withdrawn from the market because of adverse side effects. The half-life for the degradation of the diastereopmeric ester glucuronides of ketoprofen, an arylpropionic acid NSAID currently on the market, have also been derived recently at 1.45 h for the S-isomer and 0.67 h for the R-isomer [17].…”

“…The half-life for the degradation of the diastereopmeric ester glucuronides of ketoprofen, an arylpropionic acid NSAID currently on the market, have also been derived recently at 1.45 h for the S-isomer and 0.67 h for the R-isomer [17]. It is interesting that the half-life for the glucuronide of ibufenac, the arylacetic acid analogue of ibuprofen has a value of 1.1 h [17]. Ibufenac was withdrawn from the market because of hepatotoxicity in a few patients on chronic use of the drug [19].…”

An Unusual Metabolic Pathway of Sipoglitazar, a Novel Antidiabetic Agent: Cytochrome P450-Catalyzed Oxidation of Sipoglitazar Acyl Glucuronide

“…Therefore, of the two isomers, only sipoglitazar-G2 was detected in vivo. Such conversion is generally known with acyl glucuronides for which ␤-1-O-acyl glucuronide is irreversibly converted to the 2-Oisomer (Skordi et al, 2005). The rates of acyl migration depend on the …”

Role of Biotransformation Studies in Minimizing Metabolism-Related Liabilities in Drug Discovery

“…Hence, this technique could be applied to rank-order compounds within a chemical series based on the reactivity of their respective acyl-glucuronide conjugates. NMR spectrometric methods have also been introduced to monitor the stability of acyl glucuronides and elucidate the structures of their degradation products (35)(36)(37). The former task is accomplished in part by analyzing the resonance signals associated with the anomeric proton of the O-1-acyl glucuronide as a function of time.…”