A major role for cytochrome P450TB (CYP2C subfamily) in the actions of non-steroidal antiinflammatory drugs
Leemann, T.D.; Transon, C.; Bonnabry, P.; Dayer, P.
Drugs under Experimental and Clinical Research 19(5): 189-195
1993
ISSN/ISBN: 0378-6501 PMID: 8174491 Document Number: 408772
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) catalyzing 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 mu-M): diclofenac apprxeq mefenamic acid gt ibuprofen apprxeq indomethacin apprxeq piroxicam apprxeq tenoxicam gt acetylsalicylic acid apprxeq 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 of oxidize major NSAIDs and for interactions involving NSAIDs as well as other known substrates (oral anticoagulants, hypoglycemic 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.
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