Elsevier

Biochemical Pharmacology

Volume 38, Issue 24, 15 December 1989, Pages 4389-4395
Biochemical Pharmacology

Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs—1: In vitro studies of ibuprofen and flurbiprofen

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Abstract

The mechanism of inversion of the enantiomers of 2-arylpropionic acids was investigated in vitro using tissue homogenates. Crude rat liver homogenate was shown to mediate the inversion of R to S-ibuprofen, but not inversion of the S to the R-enanriomer. Inversion required CoA and ATP as cofactors. In contrast, R-ibuprofen was not inverted by homogenates of kidney or small intestine and there was no inversion of the enantiomers of flurbiprofen by any of these tissue homogenates. Longchain acyl-CoA synthetase was partially purified from rat liver microsomes and bound to Matrex Gel Red A. R-Ibuprofen was shown to be a substrate for this enzyme while S-ibuprofen and R and Sflurbiprofen were not substrates. These data are consistent with the hypothesis that the stereospecificity of inversion is controlled by the acyl-CoA synthetase. R-Ibuprofen-CoA did not racemize in either buffer solution (pH 7.4) or human plasma consistent with the hypothesis that racemization of the CoA thioesters is mediated enzymatically.

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