Vol. 26, Issue 5, 457-464, May 1998

Studies on the Stereoselective Internal Acyl Migration of Ketoprofen Glucuronides using ¹³C Labeling and Nuclear Magnetic Resonance Spectroscopy

Kazuki Akira, Tadaaki Taira, Hiroshi Hasegawa, Chiseko Sakuma, and Yoshihiko Shinohara

School of Pharmacy, Tokyo University of Pharmacy and Life Science

Internal acyl migration reactions of drug 1-O-acyl glucuronides are of interest because of their possible role in covalent binding to serum proteins and consequent allergic reactions as well as their influence on drug disposition. An approach using ¹³C labeling and nuclear magnetic resonance (NMR) spectroscopy has been used to investigate in situ the kinetics of acyl migration and hydrolysis of 1-O-acyl glucuronides of enantiomeric ketoprofens (KPs) in phosphate buffer solutions at 37°C. Apparent first-order degradation of the 1-O-acyl glucuronide labeled in the ester carbonyl carbon and the sequential appearance of 2-, 3-, and 4-O-acyl isomers as both - and -anomeric forms were observed for each enantiomer. All of the positional isomers and anomers were characterized using two-dimensional NMR spectroscopy (heteronuclear multiple bond correlation, correlated spectroscopy, totally correlated spectroscopy) of the reaction mixtures. The overall degradation rate constants (hr^-1) of (R)- and (S)-KP glucuronides were 1.07 ± 0.154 and 0.55 ± 0.034, respectively. To evaluate in detail the stereoselective reactivity, a kinetic model describing the rearrangement reactions was constructed, and the kinetics were simulated using a theoretical approach. Only the acyl migration, 12, was found to have significant stereoselectivity. The rate constants (hr^-1) for 12 migration of (R)- and (S)-KP glucuronides were 1.04 ± 0.158 and 0.52 ± 0.029, respectively. The results may suggest that (R)-KP glucuronide could be more susceptible to covalent binding to proteins via acyl migration than the corresponding antipode. This stereoselective reactivity may be responsible for the stereoselective pharmacokinetics of KP. The direct approach using ¹³C labeling and NMR spectroscopy could also provide insight into the reactivities of other labile drug acyl glucuronides and their isomeric glucuronides.