Preparation of 1-O-acylglucuronides of 13C-labelled (R)- and (S)-ketoprofens

Abstract

The preparation of enantiomeric [1‐13C]ketoprofens (KPs) and their acylglucuronides has been reported for the nuclear magnetic resonance (NMR) spectroscopic studies on the stereoselective pharmacokinetics and reactivities of KP acylglucuronides. The racemic [1‐13C]KP was prepared by a three‐step synthetic scheme from [13C]potassium cyanide in overall yield of 23 %. The racemate was optically resolved by the formation of diastereomeric amides with (R)‐(+)‐α‐phenylethylamine, separation of the amides by column chromatography on silica gel, and nonhydrolytic cleavage of the amide bond using nitrogen tetroxide. The yields of KP enantiomers were 30 % based on the racemate. The acylglucuronides of (R)‐ and (S)‐[1‐13C]KP were isolated from human urine after dosing of each labelled KP (100 mg) using preparative high‐performance liquid chromatography following Sep‐Pak C18 pretreatments. The yields of the conjugates from 0–4 h post‐dose urine were roughly 50 mg. © 1997 John Wiley & Sons, Ltd.

Kinetics of Intramolecular Acyl Migration of 1.BETA.-O-Acyl Glucuronides of (R)- and (S)-2-Phenylpropionic Acids.

“…The stereoselective difference was consistent with previously reported studies for other profens. 7,[14][15][16][17][18][19] Measurement of the 1b-O-acyl to 2-O-acyl migration rate is particularly important because the rate is considered to directly influence the extent of covalent binding to proteins. 25) Therefore, the individual rate constants for acyl migration and hydrolysis were calculated based on the kinetic model depicted in Fig.…”

“…The kinetic model assumes that the acyl migration and hydrolysis follow first order kinetics, that hydrolysis proceeds from each regioisomer and the acyl migrations are reversible except for the initial acyl migration from 1PG to 2PG. 19) Differential equations for the kinetic model are as follows:…”

“…Consequently, the diastereomeric acyl glucuronides might have distinct toxicological actions and be differentially eliminated. Although the stability of the diastereomeric acyl glucuronides has been investigated in several profens, 7,[14][15][16][17][18][19] little information is currently available on the factors that contribute to stereoselective differences in the degradation process.Enantiomeric 2-phenylpropionic acids (PAs) possess the fundamental structure of profens (Chart 1) and have been used as model substrates of profens to study the stereoselective metabolism and disposition of profens. PAs show similar pharmacokinetic properties to other profens, as observed in stereoselective isomerization and glucuronidation in rodents.…”

“…Consequently, the diastereomeric acyl glucuronides might have distinct toxicological actions and be differentially eliminated. Although the stability of the diastereomeric acyl glucuronides has been investigated in several profens, 7,[14][15][16][17][18][19] little information is currently available on the factors that contribute to stereoselective differences in the degradation process.…”

Use of 13C Labeling and NMR Spectroscopy for the Investigation of Degradation Pathways of Amadori Compounds

“…[8][9][10][11] Owing to the high specificity of detection, the application of the tracer technique enables analysis of biofluids and reaction mixtures without resorting to extraction and chromatographic separations. Therefore the decomposition and loss of compounds under sample purification and separation procedures can be minimized.…”