Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs--1. In vitro studies of ibuprofen and flurbiprofen.
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-enantiomer. 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. Long-chain 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 S-flurbiprofen 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.
Knihinicki
R D
RD
Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Darlinghurst, N.S.W., Australia.
Williams
K M
KM
Day
R O
RO
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D005480:Flurbiprofen / Q000378:metabolism*; D007052:Ibuprofen / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D007536:Isomerism; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005480:Flurbiprofen; D007052:Ibuprofen