Effects of ibuprofen enantiomers and its coenzyme A thioesters on human prostaglandin endoperoxide synthases

Abstract

1 Ibuprofen enantiomers and their respective coenzyme A thioesters were tested in human platelets and blood monocytes to determine their selectivity and potency as inhibitors of cyclo-oxygenase activity of prostaglandin endoperoxide synthase-1 (PGHS-1) and PGHS-2. 2 Human blood from volunteers was drawn and allowed to clot at 378C for 1 h in the presence of increasing concentrations of the test compounds (R-ibuprofen, S-ibuprofen, R-ibuprofenoyl-CoA, Sibuprofenoyl-CoA, NS-398). Immunoreactive (ir) thromboxane B 2 (TXB 2 ) concentrations in serum were determined by a speci®c EIA assay as an index of the cyclo-oxygenase activity of platelet PGHS-1. 3 Heparin-treated blood from the same donors was incubated at 378C for 24 h with the same concentrations of the test compounds in the presence of lipopolysaccharide (LPS, 10 mg ml 71 ). The contribution of PGHS-1 was suppressed by pretreatment of the volunteers with aspirin (500 mg; 48 h before venepuncture). As a measure of LPS induced PGHS-2 activity immunoreactive prostaglandin E 2 (irPGE 2 ) plasma concentrations were determined by a speci®c EIA assay. 4 S-ibuprofen inhibited the activity of PGHS-1 (IC 50 2.1 mM) and PGHS-2 (IC 50 1.6 mM) equally. Ribuprofen inhibited PGHS-1 (IC 50 34.9) less potently than S-ibuprofen and showed no inhibition of PGHS-2 up to 250 mM. By contrast R-ibuprofenoyl-CoA thioester inhibited PGE 2 production from LPSstimulated monocytes almost two orders of magnitude more potently than the generation of TXB 2 (IC 50 5.6 vs 219 mM). 5 Western blotting of PGHS-2 after LPS induction of blood monocytes showed a concentrationdependent inhibition of PGHS-2 protein expression by ibuprofenoyl-CoA thioesters. 6 These data con®rm that S-ibuprofen represents the active entity in the racemate with respect to cyclooxygenase activity. More importantly the data suggest a contribution of the R-enantiomer to therapeutic eects 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 why racemic ibuprofen is ranked as one of the safest non-steroidal antiin¯ammatory drugs (NSAIDs) so far determined in epidemiological studies.

Selective inhibition of Aβ42 production by NSAID R‐enantiomers

“…Their ability to lower Ab42 production occurs at doses at least an order of magnitude higher than COX inhibition. For example, ibuprofen's IC 50 for COX-1 is 2.1 lM (Neupert et al 1997; see for review Tegeder et al 2001b), well below dosing for Ab42 reduction. This implies toxicity from near complete COX inhibition will sharply curtail their use for Ab42 reduction.…”

Metabolic chiral inversion of 2-arylpropionic acid derivatives (profens)

“…Ibuprofen exists as a racemic mixture of two enantiomers: (R) and (S), which are characterised by different pharmacokinetic and pharmacodynamic profiles (Fig. 2) [6]. It has been proven in in vitro tests that (S) isomer shows about 160-times higher activity in prostaglandins inhibition compared to (R) enantiomer.…”

Potencial de biocatálise enantiosseletiva de lipases microbianas

“…interessante de medicamento que ainda é vendido como mistura racêmica. Relatos tem comprovado que a forma S do ibuprofeno é 160 vezes mais ativa que a forma R na síntese de prostaglandina in vitro 11,12 . Um grande investimento em pesquisas tem sido feito para desenvolver diferentes processos para obtenção da forma enantiomérica ativa deste fármaco.…”