A MAJOR ROLE FOR CYTOCHROME P450TB (CYP2C SUBFAMILY) IN THE ACTIONS OF NONSTEROIDAL ANTIIFLAMMATORY DRUGS

Most non-steroidal antiinflammatory drugs (NSAIDs) are extensively met abolized by liver oxidation with broad interindividual variability, bu t little is known about the nature of the enzyme(s) catalysing these r eactions. The role of specific cytochrome P450 isozymes in the formati on of the major oxidized metabolites of phenylacetic acid (diclofenac) , propionic acid (ibuprofen), fenamate (mefenamic acid) and oxicam (pi roxicam and tenoxicam) derivatives was studied in human liver microsom es using mostly selective inhibition by known substrates and inhibitor s of specific cytochrome P450 monooxygenases. A common isozyme (P450TB , CYP2C subfamily) controls the major elimination pathways of these NS AIDs. The authors have also determined, in two in vitro models of P450 TB activity, the affinity for this isozyme of other NSAIDs (acetylsali cylic acid, indomethacin, pirprofen). The NSAIDs tested displayed a hi gh affinity (5-500 mu M): diclofenac approximate to mefenamic acid > i buprofen approximate to indomethacin approximate to piroxicam approxim ate to tenoxicam > acetylsalicylic acid approximate to pirprofen. Cyto chrome P450TB therefore plays a key role in the oxidation by human liv er 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 t o oxidize major NSAIDs and for interactions involving NSAIDs as well a s other known substrates (oral anticoagulants, hypoglycaemic sulfonylu reas, phenytoin) or inhibitors (antifungals, antibacterial sulfonamide s, calcium channel blockers) of P450TB. Consequently this P450 isozyme is likely to be a major determinant of NSAIDs action.