Pharmacokinetics and pharmacodynamics of zileuton after oral administration of single and multiple dose regimens of zileuton 600mg in healthy volunteers.

The pharmacokinetics and pharmacodynamics of zileuton were determined after oral administration of single dose (600mg) and multiple dose regimens [600mg every 8 hours (q8h regimen) and 600mg every 6 hours (q6h regimen)] in 12 healthy male subjects aged 18 to 50 years. Steady-state park plasma concentration (Cmax), time to Cmax, apparent total plasma clearance, and apparent terminal phase volume of distribution values after the q8h and q6h regimens were 3.07 +/- 1.13 and 4.37 +/- 1.02 mg/L, 1.5 +/- 0.9 and 1.5 +/- 0.9 hours, 793 +/- 233 and 579 +/- 162 ml/min (47.6 and 34.7 L/h), and 179 +/- 126 and 115 +/- 29L, respectively (mean +/- SD). Trough zileuton plasma concentrations (Cmin) immediately before the morning dose were higher than Cmin immediately before the afternoon dose, suggesting a diurnal variation in the pharmacokinetics of zileuton. Accumulation of zileuton occurred with more frequent dose administration, although there was no unexpected accumulation of the parent drug or the N-dehydroxyzileuton metabolite. The q6h regimen of zileuton 600mg was superior to the q8h regimen in maintaining trough plasma concentrations of zileuton above 1.5 mg/L, corresponding to approximately 70 to 80% inhibition of leukotriene B4 biosynthesis.