Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans.
A double-blind parallel randomised study was conducted to assess the effects of multiple oral doses of zileuton (600mg every 6 hours) or matching placebo on the steady-state pharmacokinetics and pharmacodynamics of warfarin titrated to a prothrombin time of 14 to 18 seconds in 24 healthy adult male volunteers. Serial blood samples were collected for assessment of prothrombin times and R- and S-warfarin plasma concentrations. Coadministration of zileuton and warfarin had no effect on S-warfarin pharmacokinetics but statistically significantly increased mean R-warfarin plasma concentrations and decreased mean R-warfarin total oral plasma clearance compared with warfarin alone (by 15%). This stereoselective interaction was accompanied by an increase in mean morning (predose) and evening (12-hour postdose) prothrombin times from 17.5 to 19.8 seconds and 17.1 to 19.1 seconds, respectively; the corresponding changes in the placebo group were from 18.1 to 18.8 seconds and 17.3 to 17.5 seconds. Thus, multiple dose administration of zileuton appears to significantly alter steady-state R-warfarin pharmacokinetics and pharmacodynamics. Careful monitoring of prothrombin times with appropriate dose titration of warfarin is recommended with concurrent therapy of zileuton and warfarin.
Awni
W M
WM
Department of Pharmacokinetics and Biopharmaceutics, Abbott Laboratories, Abbott Park, Illinois, USA.
Hussein
Z
Z
Granneman
G R
GR
Patterson
K J
KJ
Dubé
L M
LM
Cavanaugh
J H
JH
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D001800:Blood Specimen Collection; D002851:Chromatography, High Pressure Liquid; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D011517:Prothrombin Time; D015203:Reproducibility of Results; D013237:Stereoisomerism; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
D000925:Anticoagulants; D016859:Lipoxygenase Inhibitors; D014859:Warfarin; C063449:zileuton; D006918:Hydroxyurea