Nonsteroidal antiinflammatory drugs inhibiting prostanoid efflux: as easy as ABC?

N onsteroidal antiinflammatory drugs (NSAIDs) and prostanoids continue to be fascinating research targets. Humans have been using NSAIDs in one form or another, from folk remedies through to the products of modern pharmaceutical research, for thousands of years. However, we still have not characterized all of the systems through which these drugs produce their beneficial and harmful effects (1, 2). We are certain, from seminal work carried out in the 1960s and early 1970s, that NSAIDs have the common property of inhibiting the activity of cyclooxygenase (COX), the enzyme that initiates the formation of prostanoids (1). An explosion of research in the last decade or so has led us to understand that COX exists in two forms, COX-1 and -2, and that drugs targeted against COX-2 still retain the antiinflammatory properties of traditional NSAIDs (1, 2). Because the traditional NSAIDs generally inhibit both isoforms of COX, it is the ability of NSAIDs to inhibit COX-1 that has become associated with their deleterious side effects, particularly within the gastrointestinal tract. However, this dualist approach, COX-1 good prostanoids and COX-2 bad prostanoids, does not appear to supply a full understanding of the effects of NSAIDs in vivo. For that reason, researchers have continued to look for other targets at which NSAIDs may exert effects. For example, NSAIDs have been shown to inhibit factors within inflammatory pathways, such as nuclear factor -B (3), and to elevate the production of antiinflammatory adenosine (4). Other researchers have suggested that there could be yet more COX isoforms on which the NSAIDs act (see ref. 2). Experiments with chiral NSAIDs have also shown that enantiomers inactive on COX duplicate some of the therapeutic effects of NSAIDs. For example, whereas for ketoprofen and flurbiprofen only the Sand not the R-enantiomers inhibit COX (5) at inf lammatory sites and promote gastrointestinal damage, both enantiomers are antinociceptive (6). Interestingly, although R-flurbiprofen is not a COX inhibitor, it does reduce prostaglandin production within the spinal cord, which may explain its antinociceptive properties (7). Others have found therapeutic effects of NSAID metabolites that are inactive on COX; sulindac sulfone is a clear example. The NSAID sulindac is an inactive drug metabolized to a pharmacologically active sulfide derivative, which potently inhibits COX. Sulindac is also metabolized to a sulfone derivative that is inactive against COX. However, like sulindac sulfide, sulindac sulfone both promotes cellular apoptosis and