Stereoselective Inhibition of Inducible Cyclooxygenase by Chiral Nonsteroidal Antiinflammatory Drugs

Carabaza, Assumpta; Cabré, Francesc; Rotllan, E.; Gómez, Manel; Gutiérrez, M.T.; García, Montserrat; Mauleón, David

doi:10.1002/j.1552-4604.1996.tb05040.x

Cited by 111 publications

(81 citation statements)

References 39 publications

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“…1995 . Our data also indicate that, although breaking the integrity of the cell plasma membrane should facilitate the access of metamizol to the endoplasmic reticulum and nuclear envelope, where cyclooxygenase-2 is located Ž . Morita et al, 1995 , cell purified enzymes have also been described for other Ž NSAIDs Barnett et al, 1994;Mitchell et al, 1994;. Carabaza et al, 1996 .…”

Section: Discussionmentioning

confidence: 99%

Regulation of cyclooxygenase activity by metamizol

Campos

Gregorio

Garcı́a-Nieto

et al. 1999

European Journal of Pharmacology

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The ability of metamizol to inhibit cyclooxygenase-1 and cyclooxygenase-2 activities has been evaluated using different cyclooxygenase sources. Metamizol inhibited purified cyclooxygenase-1 and cyclooxygenase-2 with an IC of about 150 mgrml. A similar IC 50 50value for cyclooxygenase-2 was obtained in lipopolysaccharide-activated broken murine macrophages. Consistent with these findings, molecular models of the complexes between cyclooxygenase-1 or cyclooxygenase-2 with 4-methylaminoantipyrine, the major active derivative of metamizol, suggested a common binding mode to both isoforms. In intact cells, however, the inhibition profiles were Ž . markedly different. The IC values of metamizol for cyclooxygenase-1 in intact bovine aortic endothelial cells BAEC cells and human 50 platelets were 1730 " 150 mgrml and 486 " 56 mgrml, respectively. Inhibition of cyclooxygenase-2 activity in murine macrophages and primary human leukocytes activated by lipopolysaccharide yielded IC values of 12 " 1.8 mgrml and 21 " 2.9 mgrml, 50 respectively. These data indicate that the IC values obtained with purified enzymes or disrupted cells cannot always be extrapolated to 50 Ž . the cyclooxygenase inhibitory activity of nonsteroidal antiinflammatory drugs NSAIDs in intact cells. The data presented here also indicate that cyclooxygenase-2 inhibition could play an important role in the pharmacological effects of metamizol. q 1999 Elsevier Science B.V. All rights reserved.Ž .

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Section: Discussionmentioning

confidence: 99%

Regulation of cyclooxygenase activity by metamizol

Campos

Gregorio

Garcı́a-Nieto

et al. 1999

European Journal of Pharmacology

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“…And, the reduction of C cr was observed for (S)-flurbiprofen but not for the (R)-enantiomer. Carabaza et al [6] examined the inhibitory effects of the flurbiprofen enantiomers on cyclooxygenase (COX)-1 and COX-2 and reported that the IC 50 values for the (R)-enantiomer were 100-fold greater than those for (S)-flurbiprofen. These are suggested to be the molecular mechanisms for the findings obtained in this study.…”

Section: Resultsmentioning

confidence: 99%

Enantioselective Effect of Flurbiprofen on Lithium Disposition in Rats

Uwai

Matsumoto²,

Kawasaki³

et al. 2017

Pharmacology

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Aims: Lithium is administered for treating bipolar disorders and is mainly excreted into urine. Nonsteroidal anti-inflammatory drugs inhibit this process. In this study, we examined the enantioselective effect of flurbiprofen on the disposition of lithium in rats. Methods: Pharmacokinetic experiments with lithium were performed. Results: Until 60 min after the intravenous administration of lithium chloride at 30 mg/kg as a bolus, 17.8% of lithium injected was recovered into the urine. Its renal clearance was calculated to be 1.62 mL/min/kg. Neither creatinine clearance (C_cr) nor pharmacokinetics of lithium was affected by the simultaneous injection of (R)-flurbiprofen at 20 mg/kg. (S)-flurbiprofen impaired the renal function and interfered with the urinary excretion of lithium. The ratio of renal clearance of lithium to C_cr was decreased by the (S)-enantiomer. Conclusion: This study clarified that the (S)-flurbiprofen but not (R)-flurbiprofen inhibited the renal excretion of lithium in rats.

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“…The results revealed that first of all, SFP potently inhibited PGE 2 production from peritoneal leukocytes stimulated with a bacterial suspension; its inhibitory activity against PGE 2 production in a rat intact cell model was a 1000-fold more potent than that of RFP and also exhibited stereoselectivity. In human polymorphonuclear cell models, SFP was shown to potently inhibit PG production (IC 50 = 2.7 nM for SFP and 400 nM for SFP, respectively; RFP/SFP inhibitory ratio = 148) [5]. Our results suggested that the inhibitory activity of SFP in human polymorphonuclear cells was nearly as effective as the inhibitory activity of SFP in the rat peritoneal leukocytes.…”

Section: Discussionmentioning

confidence: 59%

“…In the past, the 2-aryl propionic acid NSAIDs were developed in the form of a racemic mixture, even though they occurred in enantiomeric pairs differing in the COX inhibitory activity [4] [5]. Flurbiprofen (FP) is a representative drug of the chiral NSAIDs of the 2-arylpropionic acid class, and S(+)-flurbiprofen (SFP) has been shown to be a more potent COX inhibitor than the R(−)-flurbiprofen (RFP) enantiomer.…”

Section: Introductionmentioning

confidence: 99%

S(+)-Flurbiprofen Shows Potent PGE2 Inhibitory Activity in Inflammatory Cells, Superior Cell Transport Activity and Skin Permeability

Toda¹,

Sugimoto²,

Endo³

et al. 2016

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We developed a novel topical non-steroidal anti-inflammatory drug (NSAID)patch, S(+)-flurbiprofen plaster, (SFPP), containing S(+)-flurbiprofen (SFP), an enantiomer of flurbiprofen (FP).In a previous study conducted in an animal model, we showed good skin absorption and potent analgesic efficacy of SFPP. In this study, to examine the superior features, as an NSAID patch, of SFP as compared to FP and R(−)-flurbiprofen (RFP), we tested the stereospecificity of SFP actions on Prostaglandin E2 (PGE2) inhibition in rat inflammatory leukocytes and in the binding activity of the drug to cells, and also the in vitro skin permeability of the drug in the Yucatan micropig (YMP). SFP showed potent inhibitory activity on PGE2 production from peritoneal leukocytes stimulated with a bacterial suspension, as compared to RFP and FP. The half maximal (50%) inhibitory concentration (IC50) values were 14 nM for SFP, 52 nM for FP, and 17,000 nM for RFP. In the cell binding study, significant and rapid increase of SFP binding to polymorphonuclear leucocytes (PMNs) was observed at 5 min after incubation, eventually reaching a steady state. SFP showed significantly higher binding activity for the inflammatory leucocytes as compared to RFP, suggesting its superior transfer potency. The skin permeability profile of SFP, RFP and FP in the YMP model showed that the rank order of the cumulative amount of permeated compounds in the * Corresponding author. Y. Toda et al. 306skin was SFP > RFP > FP. The steady-state permeation rate (Flux) of SFP was significantly higher than that of FP (4.89 and 1.55 mg/cm 2 /h, respectively, p = 0.0068), indicating the remarkably superior skin permeability of SFP. SFP exerted potent inhibitory activity on PGE2 production and superior binding activity to the PMNs and skin permeability, as compared to FP and RFP. These results suggest that SFP possesses favorable characteristics for use as an active ingredient in the NSAID patch.

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Stereoselective Inhibition of Inducible Cyclooxygenase by Chiral Nonsteroidal Antiinflammatory Drugs

Cited by 111 publications

References 39 publications

Regulation of cyclooxygenase activity by metamizol

Regulation of cyclooxygenase activity by metamizol

Enantioselective Effect of Flurbiprofen on Lithium Disposition in Rats

S(+)-Flurbiprofen Shows Potent PGE2 Inhibitory Activity in Inflammatory Cells, Superior Cell Transport Activity and Skin Permeability

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