Bi-directional chiral inversion of ketoprofen in CD-1 mice

Abstract

The R enantiomers of some of the 2‐arylpropionic acid non‐steroidal antiinflammatory drugs (NSAIDs) are known to undergo metabolic chiral inversion to their more pharmacologically active antipodes. This process is drug and species dependent and usually unidirectional. The S to R chiral inversion, on the other hand, is rare and has been observed, in substantial extents, only for ibuprofen in guinea pigs and 2‐phenylpropionic acid in dogs. After i.p. administration of single doses of racemic ketoprofen or its optically pure enantiomers to male CD‐1 mice and subsequent study of the concentration time‐course of the enantiomers, we noticed substantial chiral inversion in both directions. Following racemic doses, no stereoselectivity in the plasma‐concentration time courses was observed. After dosing with optically pure enantiomer, the concentration of the administered enantiomer predominated during the absorption phase. During the terminal elimination phase, however, the enantiomers had the same concentrations. Our observation is suggestive of a rapid and reversible chiral inversion for ketoprofen enantiomers in mice. Chirality 9:29–31, 1997. © 1997 Wiley‐Liss, Inc.

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

“…Flurbiprofen is not significantly inverted in rats and humans, but apparently does undergo chiral inversion in horses [39,41,67]. In contrast to most species, in CD-1 mice the chiral inversion of ketoprofen has been shown to be bidirectional rather than unidirectional [68].…”

Renal d-Amino Acid Oxidase Mediates Chiral Inversion ofNG-Nitro-d-arginine

“…The metabolic chiral inversion of 2-arylpropionic acids such as ibuprofen and ketoprofen (nonsteroidal anti-inflammatory agents) has been well characterized. Chiral inversion is normally unidirectional in various species including humans, e.g., from R to S inversion for profens, whereas S to R inversion is rare (Jamali et al, 1997). The long-chain acyl-CoA synthetase and 2-arylpropionyl-CoA epimerase have been identified as key enzymes involved in the chiral inversion of 2-arylpropionic acids (Reichel et al, 1995(Reichel et al, , 1997Brugger et al, 1996).…”

Impact of chirality on the photoinduced charge transfer in linked systems containing naproxen enantiomers

“…9 Today the chiral inversion of optically active NSAIDs by AMACR is considered as a novel mechanism of their anti-cancer activity; it is believed that the enzymatically activated conversion of NSAIDs blocks the other harmful effects of an entire group of enzymes (transferases). 8,[10][11][12][13][14][15] It is worth emphasizing that this activity of NSAIDs also shows high stereoselectivity. 11,12,14 The stereoselectivity of NSAIDs in biological chemistry is investigated, specifically with respect to their main function of the inhibition of COX 2.…”

“…8,[10][11][12][13][14][15] It is worth emphasizing that this activity of NSAIDs also shows high stereoselectivity. 11,12,14 The stereoselectivity of NSAIDs in biological chemistry is investigated, specifically with respect to their main function of the inhibition of COX 2. 16 The COX 2 enzyme has several active sites: one catalytic site provides cyclization, and another one performs oxidation (involving electron transfer (ET)).…”