Formation of glycine conjugate and (–)‐(R)‐enantiomer from (+)‐(S)‐2‐phenylpropionic acid suggesting the formation of the coa thioester intermediate of (+)‐(S)‐enantiomer in dogs

Abstract

It has been proposed that the chiral inversion of the 2-arylpropionic acids is due to the stereospecific formation of the (-)-R-profenyl-CoA thioesters which are putative intermediates in the inversion. Accordingly, amino acid conjugation, for which the CoA thioesters are obligate intermediates, should be restricted to those optical forms which give rise to the (-)-R-profenyl-CoA, i.e., the racemates and the (-)-(R)-isomers. We have examined this problem in dogs with respect to 2-phenylpropionic acid(2-PPA). Regardless of the optical configuration of 2-phenylpropionic acid administered, the glycine conjugate was the major urinary metabolite and this was shown to be exclusively the (+)-(S)-enantiomer by chiral HPLC. Both (-)-(R)- and (+)-(S)-2-phenylpropionic acid were present in plasma after the administration of either antipode, and further evidence of the chiral inversion of both enantiomers was provided by the presence of some 25% of the opposite enantiomer in the free 2-phenylpropionic acid and its glucuronide excreted in urine after administration of (-)-(R)- and (+)-(S)-2-phenylpropionic acid. The (+)-(S)-enantiomer underwent chiral inversion to the (-)-(R)-antipode when incubated with dog hepatocytes. These data suggests that both enantiomers of 2-phenylpropionic acid are substrates for canine hepatic acyl CoA ligase(s) and thus undergo chiral inversion, but that the CoA thioester of only (+)-(S)-2-phenylpropionic acid is a substrate for the glycine N-acyl transferase. These studies are presently being extended to the structure and species specificity of the reverse inversion and amino acid conjugation of profen NSAIDs.

Stereospecific pharmacokinetics and toxicodynamics of ketorolac after oral administration of the racemate and optically pure enantiomers to the rat

“…Chiral R to S inversion has been observed for many profens in various speces. 25 The S to R inversion, on the other hand, is rare and is only demonstrated for ibuprofen in guinea pigs, 26 2-phenylpropionic acid in dogs, 27 and ketoprofen in mice. 28,29 The observed 6.7% of R-KT following administration of S-KT is also >1-2% of chiral impurity of the samples used.…”

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

“…Chen et al 7 reported equal extent of chiral inversion for both enantiomers of ibuprofen in guinea pigs. Tanaka et al 8 also observed that following administration of optically pure 2-phenylpropionic acid to dogs, the enantiomers concentrations reach the same level during the post-absorptive phase. These observations are consistent with those of ours and suggest the presence of a reversible metabolic inversion.…”

“…1), ibuprofen in the guinea pig 7 and 2-phenylpropionic acid in dogs. 8 The observation that ketoprofen undergoes bidirectional chiral inversion in the mouse has no apparent clinical relevance. Nevertheless, during pre-clinical stages, in choosing an animal model to study stereochemical aspects of drugs action and disposition, the information provided herein may prove useful.…”

“…The inversion of the S enantiomer, on the other hand, was substantial only in guinea pigs. In addition, Tanaka et al 8 observed a significant extent of chiral inversion in both directions following administration of 2-phenylpropionic acid to dogs. They also refer to unpublished work indicating bidirectional ketoprofen inversion in mice.…”

Direct resolution of optically active isomers on chiral packings containing ergoline skeleton. 6. Enantioseparation of profens

“…They are commercially available as racemic mixtures with the exception of (S)-naproxen. It is known that only the (S)(+)-form of the NSAIDs is biologically active, [1][2][3][4] while the (R)(−)-form is partially converted to the (S)(+)-form. This fact has been demonstrated in many recent pharmacological studies.…”