ACECLOFENAC BLOCKS PROSTAGLANDIN E-2 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 e ffects of aceclofenac on prostaglandin E-2 production by several kinds of human cells. Aceclofenac inhibited interleukin-1 beta-induced pros taglandin E-2 production by human rheumatoid synovial cells, but had n o inhibitory effect on cyclooxygenase-1 or cyclooxygenase-2 activities by itself. We also observed that part of the aceclofenac was converte d 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 diclofe nac by human polymorphonuclear leukocytes and monocytes. 4'-Hydroxy di clofenac suppressed prostaglandin E-2 production specifically by block ing cyclooxygenase-2 activity. These findings suggested that aceclofen ac 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 conclu ded that aceclofenac is shown to be a new type of non-steroidal anti-i nflammatory drug which is intracellulary converted into active metabol ites that inhibit the prostaglandin E-2 production. (C) 1997 Elsevier Science B.V.