Flurbiprofen and enantiomers in ophthalmic solution tested as inhibitors of prostanoid synthesis in human blood.
The purpose of this study was to assess the selectivity and potency of the nonsteroidal anti-inflammatory drug (NSAID), flurbiprofen, and its enantiomers in their inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). An assay was used with freshly drawn, heparinized human whole blood, incubated with 25 microM calcium ionophore A23187 during 60 min to produce thromboxane B2 (TXB2) by activity of COX-1 in platelets. Incubation with E. coli lipopolysaccharide (LPS) during 24 hr produced prostaglandin E2 (PGE2) by induction of COX-2 in monocytes, suppressing any possible contribution of COX-1 activity by the addition of acetylsalicylic acid. Concentration inhibition curves were determined with racemic, S(+), and R(-) flurbiprofen in final concentrations ranging from 10(-3) to 10(-10) M. The stereoselectivity of S(+) flurbiprofen vs. R(-) flurbiprofen, expressed as the reciprocal of the ratio of the concentrations giving 50% inhibition (IC50), is 340 for COX-1 and 56 for COX-2. The selectivity for COX-1 vs. COX-2, expressed as the reciprocal ratio of the IC50, was 32 for racemic, 16 for S(+), and 5.3 for R(-) flurbiprofen. Meloxicam in the same assay showed COX-2 selectivity with a ratio of 0.19.
van Haeringen
N J
NJ
The Netherlands Ophthalmic Research Institute, Amsterdam. n.vanhaeringen@ioi.knaw.nl
van Sorge
A A
AA
Van Delft
J L
JL
Carballosa Coré-Bodelier
V M
VM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D005480:Flurbiprofen / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000097:blood*; D008070:Lipopolysaccharides / Q000494:pharmacology; D000077239:Meloxicam; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D009883:Ophthalmic Solutions / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood*; D013237:Stereoisomerism; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009883:Ophthalmic Solutions; D013843:Thiazines; D013844:Thiazoles; D000001:Calcimycin; D013929:Thromboxane B2; D005480:Flurbiprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D000077239:Meloxicam