W. Neupert et al., EFFECTS OF IBUPROFEN ENANTIOMERS AND ITS COENZYME-A THIOESTERS ON HUMAN PROSTAGLANDIN ENDOPEROXIDE SYNTHASES, British Journal of Pharmacology, 122(3), 1997, pp. 487-492
1 Ibuprofen enantiomers and their respective coenzyme A thioesters wer
e tested in human platelets and blood monocytes to determine their sel
ectivity and potency as inhibitors of cyclo-oxygenase activity of pros
taglandin endoperoxide synthase-1 (PGHS-1) and PGHS-2. 2 Human blood f
rom volunteers was drawn and allowed to clot at 37 degrees C for 1 h i
n the presence of increasing concentrations of the test compounds (R-i
buprofen, S-ibuprofen, R-ibuprofenoyl-CoA, S-ibuprofenoyl-CoA, NS-398)
. Immunoreactive (ir) thromboxane B-2 (TXB2) concentrations in serum w
ere determined by a specific EIA assay as an index of the cyclo-oxygen
ase activity of platelet PGHS-1. 3 Heparin-treated blood from the same
donors was incubated at 37 degrees C for 24 h with the same concentra
tions of the test compounds in the presence of lipopolysaccharide (LPS
, 10 mu g ml(-1)). The contribution of PGHS-1 was suppressed by pretre
atment of the volunteers with aspirin (500 mg; 48 h before venepunctur
e). As a measure of LPS induced PGHS-2 activity immunoreactive prostag
landin E-2 (irPGE(2)) plasma concentrations were determined by a speci
fic EIA assay. 4 S-ibuprofen inhibited the activity of PGHS-1 (IC50 2.
1 mu M) and PGHS-2 (IC50 1.6 mu M) equally. R-ibuprofen inhibited PGHS
-1 (IC50 34.9) less potently than S-ibuprofen and showed no inhibition
of PGHS-2 up to 250 mu M. By contrast R-ibuprofenoyl-CoA thioester in
hibited PGE(2) production from LPS-stimulated monocytes almost two ord
ers of magnitude more potently than the generation of TXB2 (IC50 5.6 v
s 219 mu M). 5 Western blotting of PGHS-2 after LPS induction of blood
monocytes showed a concentration-dependent inhibition of PGHS-2 prote
in expression by ibuprofenoyl-CoA thioesters. 6 These data confirm tha
t S-ibuprofen represents the active entity in the racemate with respec
t to cyclooxygenase activity. More importantly the data suggest a cont
ribution of the R-enantiomer to therapeutic effects not only by chiral
inversion to S-ibuprofen but also via inhibition of induction of PGHS
-2 mediated by R-ibuprofenoyl-CoA thioester. 7 The data may explain wh
y racemic ibuprofen is ranked as one of the safest non-steroidal antii
nflammatory drugs (NSAIDs) so far determined in epidemiological studie
s.