Effect of diclofenac sodium, tolfenamic acid and indomethacin on the production of superoxide induced by N-formyl-methionyl-leucyl-phenylalanine in normal human polymorphonuclear leukocytes.
The effect of three non-steroidal anti-inflammatory drugs, diclofenac, indomethacin and tolfenamic acid, on the production of superoxide (O2-), by normal human polymorphonuclear leukocytes (PMNL) was studied, in vitro. The cells were activated with N-formyl-methionyl-leucyl-phenylalanine (FMLP) and O2- production was measured as superoxide dismutase inhibitable cytochrome c reduction. Cell viability was checked with assays of liberated LDH. Concentrations of the drugs considerably higher than those of therapeutic plasma were required to inhibit O2- production. The drug concentrations producing a 50% inhibition (IC50) of total O2- production were: diclofenac 2.7 X 10(-4) M, indomethacin 4.0 X 10(-4) M and tolfenamic acid 4.2 X 10(-4) M. At drug concentrations causing a significant suppression of O2- generation, diclofenac showed a slight and tolfenamic acid a marked inhibition of [3H]FMLP binding to its cellular receptor; indomethacin has earlier been shown to inhibit FMLP-binding slightly. No dismutating activity of the drugs could be demonstrated. It is concluded that the inhibition of O2- production is due to a combined effect on FMLP binding and on cellular O2- metabolism. Because of the high drug concentrations required to inhibit O2- production, this phenomenon is obviously of little significance for the anti-inflammatory effect obtained with therapeutic doses of the drugs studied.
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001667:Binding, Competitive; D003864:Depression, Chemical; D004008:Diclofenac / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000032:analysis; D013481:Superoxides / Q000378:metabolism*; D014316:Tritium; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D062367:ortho-Aminobenzoates; D014316:Tritium; D013481:Superoxides; D004008:Diclofenac; C009500:tolfenamic acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013482:Superoxide Dismutase; D007213:Indomethacin