title: Effect of itraconazole on the pharmacokinetics and pharmacodynamics of a single oral dose of brotizolam.
abstract: OBJECTIVE
  To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP)3A4, on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam.
  
  
  METHODS
  In this randomized, double-blind, cross-over trial 10 healthy male subjects received either itraconazole 200 mg or matched placebo once daily for 4 days. On day 4, a single 0.5 mg dose of brotizolam was administered orally. Plasma concentrations of brotizolam were followed up to 24 h, together with assessment of psychomotor function measured by the digit symbol substitution test (DSST), visual analogue scales and UKU side-effect rating scale.
  
  
  RESULTS
  Itraconazole significantly (P < 0.001) decreased the apparent oral clearance (CL/F) (16.47 +/- 4.3 vs 3.91 +/- 2.1), increased the area under the concentration-time curves (AUC) from 0 h to 24 h (28.37 +/- 10.8 vs 68.71 +/- 24.1 ng ml h(-1)), and prolonged the elimination half-life (4.56 +/- 1.4 vs 23.27 +/- 10.3 h) of brotizolam. The AUC(0,24 h) of the DSST (P < 0.001) and the item 'sleepiness' of UKU (P < 0.05) were significantly decreased.
  
  
  CONCLUSIONS
  Itraconazole increases plasma concentrations of brotizolam probably via its inhibitory effect on CYP3A4 brotizolam metabolism.
authors.affiliation: Clinical Research Center, Hirosaki University Hospital, Hirosaki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Osanai
authors.forename: T
authors.initials: T
authors.lastname: Ohkubo
authors.forename: N
authors.initials: N
authors.lastname: Yasui
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.forename: S
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001381:Azepines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004311:Double-Blind Method; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male; D011597:Psychomotor Performance / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D001381:Azepines; D065607:Cytochrome P-450 Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D017964:Itraconazole; C020960:brotizolam; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human