title: Influence of plasma protein on the potencies of inhibitors of cyclooxygenase-1 and -2.
abstract: It is widely believed that the potencies of nonsteroid anti-inflammatory drugs (NSAIDs) as inhibitors of cyclooxygenase (COX) are influenced by protein binding in the extracellular fluid, since NSAIDs are bound to circulating albumin by well over 95%. This is an important point because the protein concentrations in synovial fluid and the central nervous system, which are sites of NSAID action, are markedly different from those in plasma. Here we have used a modified whole-blood assay to compare the potencies of aspirin, celecoxib, diclofenac, indomethacin, lumiracoxib, meloxicam, naproxen, rofecoxib, sodium salicylate, and SC560 as inhibitors of COX-1 and COX-2 in the presence of differing concentrations of protein. The potencies of diclofenac, naproxen, rofecoxib, and salicylate, but not aspirin, celecoxib, indomethacin, lumiracoxib, meloxicam, or SC560, against COX-1 (human platelets) increased as protein concentrations were reduced. Varying protein concentrations did not affect the potencies of any of the drugs against COX-2, with the exception of sodium salicylate (A549 cells). Clearly, our findings show that the selectivity of inhibitors for COX-1 and COX-2, which are taken to be linked to their efficacy and side effects, may change in different extracellular fluid conditions. In particular, selectivity in one body compartment does not demonstrate selectivity in another. Thus, whole-body safety or toxicity cannot be linked to one definitive measure of COX selectivity.
authors.affiliation: The William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK. t.d.warner@qmul.ac.uk
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.forename: Ivana
authors.initials: I
authors.lastname: Vojnovic
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D001241:Aspirin / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D001798:Blood Proteins / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D000068579:Celecoxib; D002460:Cell Line / Q000187:drug effects; D002556:Cerebrospinal Fluid Proteins / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D004008:Diclofenac / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology / Q000031:analogs & derivatives; D015232:Dinoprostone / Q000096:biosynthesis / Q000097:blood / Q000134:cerebrospinal fluid; D006801:Humans; D007213:Indomethacin / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007783:Lactones / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D000077239:Meloxicam; D009288:Naproxen / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D009928:Organ Specificity; D009930:Organic Chemicals / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D011485:Protein Binding; D011720:Pyrazoles / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D012980:Sodium Salicylate / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D013449:Sulfonamides / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D013450:Sulfones / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D013582:Synovial Fluid / Q000378:metabolism; D013843:Thiazines / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D013844:Thiazoles / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D013928:Thromboxane A2 / Q000097:blood
chemical_list: D001798:Blood Proteins; D002556:Cerebrospinal Fluid Proteins; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007476:Ionophores; D007783:Lactones; D009930:Organic Chemicals; D011720:Pyrazoles; C115461:SC 560; D013449:Sulfonamides; D013450:Sulfones; D013843:Thiazines; D013844:Thiazoles; C116926:rofecoxib; D004008:Diclofenac; D000001:Calcimycin; D013928:Thromboxane A2; D009288:Naproxen; D051545:Cyclooxygenase 1; D000068579:Celecoxib; D015232:Dinoprostone; D001241:Aspirin; D002118:Calcium; C473384:lumiracoxib; D000077239:Meloxicam; D012980:Sodium Salicylate; D007213:Indomethacin