title: Pharmacokinetics and pharmacodynamics of zileuton after oral administration of single and multiple dose regimens of zileuton 600mg in healthy volunteers.
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.
authors.affiliation: Pharmacokinetics and Biopharmaceutics Department, Abbott Laboratories, Abbott Park, Illinois, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Awni
authors.forename: R A
authors.initials: RA
authors.lastname: Braeckman
authors.forename: G R
authors.initials: GR
authors.lastname: Granneman
authors.forename: G
authors.initials: G
authors.lastname: Witt
authors.forename: L M
authors.initials: LM
authors.lastname: Dubé
mesh_terms: D000293:Adolescent; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005215:Fasting; D006801:Humans; D006900:Hydroxylation; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism; D014508:Urea / Q000031:analogs & derivatives / Q000097:blood; D044465:White People
chemical_list: D016859:Lipoxygenase Inhibitors; C097393:N-dehydroxyzileuton; D007975:Leukotriene B4; D014508:Urea; C063449:zileuton; D006918:Hydroxyurea