Aceclofenac blocks prostaglandin E2 production following its intracellular conversion into cyclooxygenase inhibitors.
Aceclofenac, 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid, is a novel non-steroidal anti-inflammatory drug. We investigated the effects of aceclofenac on prostaglandin E2 production by several kinds of human cells. Aceclofenac inhibited interleukin-1beta-induced prostaglandin E2 production by human rheumatoid synovial cells, but had no inhibitory effect on cyclooxygenase-1 or cyclooxygenase-2 activities by itself. We also observed that part of the aceclofenac was converted into diclofenac, the cyclooxygenase-1 and cyclooxygenase-2 inhibitor, when aceclofenac was incubated with human rheumatoid synovial cells. Aceclofenac was also converted into diclofenac and 4'-hydroxy diclofenac by human polymorphonuclear leukocytes and monocytes. 4'-Hydroxy diclofenac suppressed prostaglandin E2 production specifically by blocking cyclooxygenase-2 activity. These findings suggested that aceclofenac can be metabolized to cyclooxygenase inhibitors (diclofenac and/or 4'-hydroxy diclofenac) by these inflammatory cells. Although detailed examinations in non-inflammatory cells remain to be studied, we concluded that aceclofenac is shown to be a new type of non-steroidal anti-inflammatory drug which is intracellulary converted into active metabolites that inhibit the prostaglandin E2 production.
Yamazaki
R
R
Yakult Central Institute for Microbiological Research, Tokyo, Japan.
Kawai
S
S
Matsuzaki
T
T
Kaneda
N
N
Hashimoto
S
S
Yokokura
T
T
Okamoto
R
R
Koshino
T
T
Mizushima
Y
Y
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
C108035:4'-hydroxyaceclofenac; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D004008:Diclofenac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C108036:4'-hydroxydiclofenac; C056498:aceclofenac