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.