Leemann T D, Transon C, Bonnabry P, Dayer P
Department of Medicine, University Hospital, Geneva, Switzerland.
Drugs Exp Clin Res. 1993;19(5):189-95.
Most non-steroidal antiinflammatory drugs (NSAIDs) are extensively metabolized by liver oxidation with broad interindividual variability, but little is known about the nature of the enzyme(s) catalysing these reactions. The role of specific cytochrome P450 isozymes in the formation of the major oxidized metabolites of phenylacetic acid (diclofenac), propionic acid (ibuprofen), fenamate (mefenamic acid) and oxicam (piroxicam and tenoxicam) derivatives was studied in human liver microsomes using mostly selective inhibition by known substrates and inhibitors of specific cytochrome P450 monooxygenases. A common isozyme (P450TB, CYP2C subfamily) controls the major elimination pathways of these NSAIDs. The authors have also determined, in two in vitro models of P450TB activity, the affinity for this isozyme of other NSAIDs (acetylsalicylic acid, indomethacin, pirprofen). The NSAIDs tested displayed a high affinity (5-500 microM): diclofenac approximately mefenamic acid > ibuprofen approximately indomethacin approximately piroxicam approximately tenoxicam > acetylsalicylic acid approximately pirprofen. Cytochrome P450TB therefore plays a key role in the oxidation by human liver of major NSAIDs from various chemical classes. Inhibition data and chemical structure similarities suggest that many other NSAIDs may be substrates of this isozyme as well. P450TB appears to be a common site both for the control of interindividual differences in the capacity to oxidize major NSAIDs and for interactions involving NSAIDs as well as other known substrates (oral anticoagulants, hypoglycaemic sulfonylureas, phenytoin) or inhibitors (antifungals, antibacterial sulfonamides, calcium channel blockers) of P450TB. Consequently this P450 isozyme is likely to be a major determinant of NSAIDs action.
大多数非甾体抗炎药（NSAIDs）在肝脏中通过氧化作用广泛代谢，个体间差异很大，但对于催化这些反应的酶的性质了解甚少。使用已知的细胞色素P450单加氧酶的底物和抑制剂进行选择性抑制，在人肝微粒体中研究了特定细胞色素P450同工酶在苯乙酸（双氯芬酸）、丙酸（布洛芬）、芬那酸（甲芬那酸）和昔康（吡罗昔康和替诺昔康）衍生物主要氧化代谢产物形成中的作用。一种常见的同工酶（P450TB，CYP2C亚家族）控制着这些NSAIDs的主要消除途径。作者还在P450TB活性的两种体外模型中测定了其他NSAIDs（乙酰水杨酸、吲哚美辛、吡洛芬）对该同工酶的亲和力。所测试的NSAIDs显示出高亲和力（5 - 500 microM）：双氯芬酸≈甲芬那酸＞布洛芬≈吲哚美辛≈吡罗昔康≈替诺昔康＞乙酰水杨酸≈吡洛芬。因此，细胞色素P450TB在人肝脏对各种化学类别的主要NSAIDs的氧化中起关键作用。抑制数据和化学结构相似性表明，许多其他NSAIDs也可能是该同工酶的底物。P450TB似乎是控制个体间氧化主要NSAIDs能力差异以及涉及NSAIDs与其他已知底物（口服抗凝剂、降血糖磺脲类、苯妥英）或P450TB抑制剂（抗真菌药、抗菌磺胺类、钙通道阻滞剂）相互作用的共同位点。因此，这种P450同工酶可能是NSAIDs作用的主要决定因素。
