Metabolic stereoisomeric inversion of 2-arylpropionic acids. On the mechanism of ibuprofen epimerization in rats

Abstract

Kinetic and mechanistic studies are described for the metabolic stereoisomeric inversion of R-ibuprofen in rats. After oral administration of R-ibuprofen to rats, the plasma levels and enantiomeric compositions of ibuprofen and its major metabolite were monitored. Although individual animals exhibited great variations in metabolic rates, the concentration ratios of the S- and R-enantiomers of ibuprofen and also its metabolite remained roughly unchanged within 90 min. Even though it is generally believed that this bioconversion is strictly stereospecific in nature, chromatographic analysis revealed that S-ibuprofen also underwent metabolic inversion, however, at a much slower rate, than its R counterpart. The inversion mechanism was assessed by monitoring the loss of labeled deuterium from specifically deuterated ibuprofen. No significant isotope effect was observed for the metabolism of these deuterated derivatives. One deuterium atom was lost in the S-ibuprofen resulted from R-[2-2H]ibuprofen metabolism, whereas all the three deuterium atoms were retained when R-[3,3,3-2H3]ibuprofen was used as the substrate. These results reinforce the proposed mechanism that the inversion proceeds via a thioester carbanion intermediate. The pKa of the alpha-methine proton of ibuprofen N-acetylcysteamine thioester was shown to be 10.34 +/- 0.06, which excludes the possibility that ibuprofen may undergo inversion through the nonenzymatic isomerization of its acyl thioester.