Stereospecific pH-dependent degradation kinetics of R- and S-naproxen-beta-l-O-acyl-glucuronide.
The hydrolysis and acyl migration of biosynthetic S-naproxen-beta-l-O-acyl glucuronide (I) and R-naproxen-beta-l-O-acyl glucuronide (II) was followed by HPLC. Nine first-order kinetic rate constants for the hydrolysis and acyl migration between the beta-l-O-acyl glucuronide, its alpha/beta-2, alpha/beta-3-, alpha/beta-4-, and alpha-1-O-acyl isomers and naproxen aglycone were determined for I and II at pH 7.00, 7.40 and 8.00 at 37 degrees 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 alpha-l-O-acyl isomer was 10:1 (2-O-acyl isomer:alpha-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-beta-l-O-acyl glucuronide acyl-migrated isomers, suggesting that these findings may be general for acyl-migrated beta-l-O-acyl glucuronides of enantiomeric 2-arylpropionic acids.
Mortensen
Rasmus Worm
RW
Department of Analytical and Pharmaceutical Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark. rasmus.mortensen@leo-pharma.com
Sidelmann
Ulla Grove
UG
Tjørnelund
Jette
J
Hansen
Steen Honoré
SH
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005260:Female; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007660:Ketoprofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D009288:Naproxen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013552:Swine
D020719:Glucuronides; C430408:naproxen glucuronide; D009288:Naproxen; C044223:ketoprofen glucuronide; D007660:Ketoprofen