title: Effect of fluconazole on the pharmacokinetics and pharmacodynamics of oral and rectal bromazepam: an application of electroencephalography as the pharmacodynamic method.
abstract: Quantitative analysis of electroencephalography (EEG) is used increasingly to evaluate the pharmacodynamics of benzodiazepines. The present study aimed to apply the EEG method as well as more traditional approaches to an interaction study of bromazepam and fluconazole. Twelve healthy male volunteers participated in a randomized, double-blind, four-way crossover study. The subjects received single oral or rectal doses of bromazepam (3 mg) after 4-day pretreatment of oral fluconazole (100 mg daily) or its placebo. Plasma bromazepam concentrations were measured before and 0.5, 1, 2, 3, 4, 6, 12, 22, 46, and 70 hours after bromazepam administration. Pharmacodynamic effects of bromazepam were assessed using self-rated drowsiness, continuous number addition test, and EEG. Fluconazole caused no significant changes in pharmacokinetics and pharmacodynamics of oral or rectal bromazepam. Rectal administration significantly increased AUC (1.7-fold, p < 0.0001) and Cmax (1.6-fold, p < 0.0001) of bromazepam. These changes following rectal dose may be due to avoidance of degradation occurring in the gastrointestinal tract. Rectal bromazepam also increased the area under the effect curves assessed by EEG (p < 0.05) and subjective drowsiness (p < 0.05). EEG effects were closely correlated with mean plasma bromazepam concentrations (r = 0.92, p < 0.001 for placebo; r = 0.89, p < 0.0001 for fluconazole). Thus, the EEG method provided pharmacodynamic data that clearly reflected the pharmacokinetics of bromazepam.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Oita Medical University, Japan.
authors.forename: Yasukiyo
authors.initials: Y
authors.lastname: Ohtani
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kotegawa
authors.forename: Kimiko
authors.initials: K
authors.lastname: Tsutsumi
authors.forename: Takuya
authors.initials: T
authors.lastname: Morimoto
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Hirose
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Nakano
mesh_terms: D000284:Administration, Oral; D000285:Administration, Rectal; D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001960:Bromazepam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004311:Double-Blind Method; D004347:Drug Interactions; D004569:Electroencephalography / Q000187:drug effects*; D015725:Fluconazole / Q000494:pharmacology*; D018757:GABA Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D011597:Psychomotor Performance / Q000187:drug effects; D012894:Sleep Stages / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D018757:GABA Modulators; D015725:Fluconazole; D001960:Bromazepam