The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers.
OBJECTIVE
Bromazepam, an anti-anxiety agent, has been reported to be metabolized by cytochrome P(450) (CYP). However, the enzyme responsible for the metabolism of bromazepam has yet to be determined. The purpose of this study was to examine whether the inhibition of CYP3A4 produced by itraconazole alters the pharmacokinetics and pharmacodynamics of bromazepam.


METHODS
Eight healthy male volunteers participated in this randomized double-blind crossover study. The subjects received a 6-day treatment of itraconazole (200 mg daily) or its placebo. On day 4 of the treatment, each subject received a single oral dose of bromazepam (3 mg). Blood samplings for drug assay were performed up to 70 h after bromazepam administration. The time course of the pharmacodynamic effects of bromazepam on the central nervous system was assessed using a subjective rating of sedation, continuous number addition test and electroencephalography up to 21.5 h after bromazepam administration.


RESULTS
Itraconazole caused no significant changes in the pharmacokinetics and pharmacodynamics of bromazepam. The mean (+/-SD) values of area under the plasma concentration-time curve and elimination half-life for placebo versus itraconazole were 1328+/-330 ng h/ml versus 1445+/-419 ng h/ml and 32.1+/-9.3 h versus 31.1+/-8.4 h, respectively.


CONCLUSIONS
The pharmacokinetics and pharmacodynamics of bromazepam were not affected by itraconazole, suggesting that CYP3A4 is not involved in the metabolism of bromazepam to a major extent. It is likely that bromazepam can be used in the usual doses for patients receiving itraconazole or other CYP3A4 inhibitors.
D000328:Adult; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001960:Bromazepam / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male
D014151:Anti-Anxiety Agents; D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D017964:Itraconazole; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D001960:Bromazepam