Stereoselective metabolism of anti-inflammatory 2-arylpropionates

Abstract

2-Arylpropionic acids (profens) are a major group of non-steroidal anti-inflammatory drugs. These compounds exist in two enantiomeric forms due to the presence of an asymmetric carbon atom alpha to the carbonyl function. In vitro tests have shown that the anti-prostaglandin synthetase activity of profens resides almost exclusively in the (+)-(S)-enantiomers, yet all profens except naproxen are marketed as racemates. The profens exhibit enantioselective pharmacokinetics, the most intriguing aspect of which is their unidirectional chiral inversion from the (-)-(R)- to the (+)-(S)-enantiomer. Since the transformation goes from the inactive to the pharmacologically active form, the (R)-enantiomer can be considered as a prodrug of its (S)-antipode. The available evidence suggests that this reaction proceeds via the formation of the acyl-CoA thioester of the 2-arylpropionates. Hutt and Caldwell have reviewed the literature describing this unusual metabolic process. The purpose of this paper is to present more recent findings from in vivo and in vitro studies and to summarize actual knowledge concerning the mechanism of the metabolic chiral inversion of profens.