The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences

Biochem Pharmacol. 1988 Jan 1;37(1):105-14. doi: 10.1016/0006-2952(88)90762-9.

Abstract

The 2-arylpropionic acids are currently an important group of non-steroidal anti-inflammatory agents. They contain a chiral centre, and in vitro studies on inhibition of prostaglandin synthesis show that their activity resides almost exclusively in the S(+)-isomers. However, this stereoselectivity of action is not manifest in vivo, due to the thus-far-unique unidirectional metabolic inversion of the chiral centre from the inactive R(-)-isomers to the S(+)-antipodes. Available evidence strongly suggests that this reaction proceeds via the formation of the acyl CoA thioesters of the 2-arylpropionates, but the participation of enzyme(s) in the inversion process remains uncertain. Although the chiral inversion is seemingly a general feature of the fate of 2-arylpropionates, there do occur important combinations of acid and species where the reaction is not extant. The stereochemistry of the chiral centre of these acids also influences other aspects of their disposition, including the oxidative metabolism of the aryl/arylakyl moiety, glucuronidation of the -COOH group and plasma protein binding, and the importance of certain of these becomes more evident when renal function is impaired. The biological consequences of the metabolic chiral inversion and enantioselective disposition of the 2-arylpropionates have been summarized in terms of their implications for the development and use of safer and more effective drugs of this class.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics*
  • Humans
  • Kidney / metabolism
  • Molecular Conformation
  • Phenylpropionates / pharmacokinetics*
  • Protein Binding
  • Stereoisomerism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Phenylpropionates