The Pharmacokinetic and Pharmacodynamic Interactions Between the 5-lipoxygenase Inhibitor Zileuton and the Cyclo-oxygenase Inhibitor Naproxen in Human Volunteers

The potential pharmacokinetic and pharmacodynamic interactions between zileuton, a 5-lipoxygenase inhibitor, and naproxen, a nonsteroidal anti-inflammatory drug that acts as a cyclo-oxygenase inhibitor, have been investigated in 24 healthy volunteers. Coadministration of these 2 drugs had no effect upon the plasma concentration-time curves of either zileuton (800mg) or naproxen (500mg) when compared with each drug administered alone. Both naproxen plasma concentrations during the elimination phase and area under the plasma concentration-time curve values were statistically significantly raised upon coadministration with zileuton, when compared with naproxen alone. However, these differences in these 2 values were sufficiently small to be of no clinical significance. There is no evidence that the combination of zileuton and naproxen had an effect on leukotriene B4 levels that was different from the inhibitory effect of zileuton alone, or had an effect on serum thromboxane B2 levels that was different from the effect of naproxen alone. Moreover, inhibition of the 5-lipoxygenase pathway by zileuton did not appear to aggravate the gastrointestinal adverse events commonly associated with naproxen administration. It is concluded that zileuton and naproxen may be coadministered with minimal risk of a clinically significant interaction.