Stereospecific pH‐dependent degradation kinetics of R‐ and S‐naproxen‐β‐l‐ O ‐acyl‐glucuronide

The hydrolysis and acyl migration of biosynthetic S‐naproxen‐β‐l‐ O ‐acyl glucuronide (I) and R‐naproxen‐β‐l‐ O ‐acyl glucuronide (II) was followed by HPLC. Nine first‐order kinetic rate constants for the hydrolysis and acyl migration between the β‐l‐ O ‐acyl glucuronide, its α/β‐2, α/β‐3‐, α/β‐4‐, and α‐1‐ O ‐acyl isomers and naproxen aglycone were determined for I and II at pH 7.00, 7.40 and 8.00 at 37°C by kinetic simulation. For I the 3‐ O ‐acyl isomer was the most stable isomer as the pseudo‐equilibrium ratio for the major acyl‐migrated isomers was 1:1.5:0.9 (2‐ O ‐acyl isomer:3‐ O ‐acyl isomer:4‐ O ‐acyl isomer). The 3‐ and 4‐ O ‐acyl isomers of II were equally stable as the pseudo‐equilibrium ratio for the major acyl‐migrated isomers was 1:1.4:1.4 (2‐ O ‐acyl isomer:3‐ O ‐acyl isomer:4‐ O ‐acyl isomer). For both I and II, the pseudo‐equilibrium ratio between the major 2‐ O ‐acyl isomer and the minor α‐l‐ O ‐acyl isomer was 10:1 (2‐ O ‐acyl isomer:α‐l‐ O ‐acyl isomer). The pseudo‐equilibrium found for the major acyl‐migrated isomers of I and II in the present study corresponds with the pattern previously published for R‐ and S‐ketoprofen‐β‐l‐ O ‐acyl glucuronide acyl‐migrated isomers, suggesting that these findings may be general for acyl‐migrated β‐l‐ O ‐acyl glucuronides of enantiomeric 2‐arylpropionic acids. Chirality 14:305–312, 2002. © 2002 Wiley‐Liss, Inc.