title: Pharmacokinetics and pharmacodynamics of single and multiple oral doses of a novel 5-lipoxygenase inhibitor (ABT-761) in healthy volunteers.
abstract: OBJECTIVE
  This study evaluated the safety, pharmacokinetics and pharmacodynamics of ABT-761 [R(+)-N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-1- methyl-2-propynyl]-N-hydroxyurea], a new N-hydroxyurea analog.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled, single- and multiple-dose (15-day) study of ABT-761 (50 to 200 mg/day) in healthy, nonsmoking adult male volunteers. The pharmacokinetics were evaluated by investigation of the time- and dose-dependent effects of ABT-761, and the pharmacologic selectivity of ABT-761 was evaluated based on calcium ionophore-stimulated leukotriene B4 (LTB4) and thromboxane B2 (TXB2) biosynthesis ex vivo in whole blood.
  
  
  RESULTS
  After single and multiple doses, mean observed time to reach maximum concentration values of ABT-761 ranged from 4.0 to 7.5 hours. Mean values for maximum concentration and area under the plasma concentration-time curve from 0 to 24 hours increased approximately linearly with dose. Mean terminal half-life and apparent volume of distribution during the terminal elimination phase of ABT-761 ranged from 15.4 to 17.8 hours and 69.5 to 78.9 L, respectively, and was dose independent. Steady state was reached on day 11 after multiple dosing. Less than 0.05% of unchanged ABT-761 was recovered in urine within the 24-hour period after day 15 dosing. Population ABT-761 plasma concentration at which 50% of the maximum possible inhibition was observed for LTB4 inhibition was 0.24 microgram/ml. No differences in mean TXB2 inhibition were observed between the subjects receiving ABT-761 and placebo.
  
  
  CONCLUSIONS
  These results indicate that ABT-761 is a potent and selective inhibitor of 5-lipoxygenase and the pharmacokinetics of ABT-761 are time and dose independent between 50 and 200 mg/day after single and multiple dosing.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Abbott Laboratories, Abbott Park, IL 60064-3500, USA. shekman.wong@abbott.com
authors.forename: S L
authors.initials: SL
authors.lastname: Wong
authors.forename: J
authors.initials: J
authors.lastname: Drajesk
authors.forename: M
authors.initials: M
authors.lastname: Chang
authors.forename: C
authors.initials: C
authors.lastname: Lanni
authors.forename: G
authors.initials: G
authors.lastname: Witt
authors.forename: R
authors.initials: R
authors.lastname: Hansen
authors.forename: W M
authors.initials: WM
authors.lastname: Awni
mesh_terms: D000284:Administration, Oral; D000328:Adult; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008297:Male; D012016:Reference Values
chemical_list: D016859:Lipoxygenase Inhibitors; C096921:atreleuton; D006918:Hydroxyurea