Warner Timothy D, Vojnovic Ivana, Bishop-Bailey David, Mitchell Jane A
The William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK.
FASEB J. 2006 Mar;20(3):542-4. doi: 10.1096/fj.05-4434fje. Epub 2006 Jan 10.
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.
人们普遍认为，非甾体抗炎药（NSAIDs）作为环氧化酶（COX）抑制剂的效力受细胞外液中蛋白质结合的影响，因为NSAIDs与循环中的白蛋白结合率超过95%。这是一个重要的观点，因为NSAIDs发挥作用的部位——滑液和中枢神经系统中的蛋白质浓度与血浆中的明显不同。在此，我们使用改良的全血分析法，比较阿司匹林、塞来昔布、双氯芬酸、吲哚美辛、鲁米昔布、美洛昔康、萘普生、罗非昔布、水杨酸钠和SC560在不同蛋白质浓度下作为COX-1和COX-2抑制剂的效力。双氯芬酸、萘普生、罗非昔布和水杨酸盐（而非阿司匹林、塞来昔布、吲哚美辛、鲁米昔布、美洛昔康或SC560）对COX-1（人血小板）的效力随着蛋白质浓度的降低而增加。除水杨酸钠（A549细胞）外，不同的蛋白质浓度并未影响任何一种药物对COX-2的效力。显然，我们的研究结果表明，抑制剂对COX-1和COX-2的选择性（这被认为与其疗效和副作用相关）在不同的细胞外液条件下可能会发生变化。特别是，在一个身体腔室中的选择性并不能表明在另一个腔室中的选择性。因此，全身安全性或毒性不能与COX选择性的一种明确测量方法相关联。
