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Stereospecific pH‐dependent degradation kinetics of R‐ and S‐naproxen‐β‐l‐ O ‐acyl‐glucuronide
Author(s) -
Mortensen Rasmus Worm,
Sidelmann Ulla Grove,
Tjørnelund Jette,
Hansen Steen Honoré
Publication year - 2002
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.10047
Subject(s) - chemistry , acyl group , stereochemistry , stereospecificity , acylation , hydrolysis , nucleophilic acyl substitution , cis–trans isomerism , kinetics , stereoisomerism , medicinal chemistry , organic chemistry , catalysis , alkyl , physics , quantum mechanics
Abstract 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.