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

Clin Pharmacokinet. 1995;29 Suppl 2:22-33. doi: 10.2165/00003088-199500292-00005.

Abstract

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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Chromatography, High Pressure Liquid
  • Circadian Rhythm
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Fasting
  • Humans
  • Hydroxylation
  • Hydroxyurea / administration & dosage
  • Hydroxyurea / analogs & derivatives*
  • Hydroxyurea / pharmacokinetics
  • Hydroxyurea / pharmacology
  • Leukotriene B4 / biosynthesis
  • Lipoxygenase Inhibitors / administration & dosage
  • Lipoxygenase Inhibitors / pharmacokinetics*
  • Lipoxygenase Inhibitors / pharmacology
  • Male
  • Middle Aged
  • Stereoisomerism
  • Urea / analogs & derivatives
  • Urea / blood
  • Whites

Substances

  • Lipoxygenase Inhibitors
  • N-dehydroxyzileuton
  • Leukotriene B4
  • Urea
  • zileuton
  • Hydroxyurea