Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole.
BACKGROUND
Triazolam is metabolized by CYP3A4 isozyme. Ketoconazole and itraconazole may seriously interact with some of the substrates of CYP3A4 (e.g., terfenadine); hence their possible interaction with triazolam in humans is important to uncover.


METHODS
In this double-blind, randomized, three-phase crossover study, the interaction between ketoconazole, itraconazole, and triazolam was investigated. Nine healthy young volunteers received either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo (control phase) orally once a day for 4 days. On day 4, each ingested a single 0.25 mg dose of triazolam. Plasma concentrations of triazolam and antimycotics were determined, and pharmacodynamic effects were measured up to 17 hours.


RESULTS
On average, ketoconazole and itraconazole increased the area under the triazolam concentration-time curve [AUC(0-infinity)] 22-fold and 27-fold (p < 0.001), the peak concentrations threefold (p < 0.001), and the elimination half-life sixfold and sevenfold (p < 0.001), respectively. In seven of the nine subjects, even the maximum concentration of triazolam in plasma was lower without the antimycotics than were the 17-hour concentrations during the ketoconazole and itraconazole phases. All pharmacodynamic effects (e.g., the Digit Symbol Substitution Test) revealed a significant difference between the antimycotic and placebo phases.


CONCLUSIONS
Both ketoconazole and itraconazole seriously affect the pharmacokinetics of triazolam and increase the intensity and duration of its effects. Inhibition of CYP3A4 during the absorption and elimination phases of triazolam seems to explain the interaction observed. Because of the potentially hazardous consequences of this interaction, triazolam should be avoided if patients are using ketoconazole or itraconazole.
Varhe
A
A
Department of Clinical Pharmacology, University of Helsinki, Finland.
Olkkola
K T
KT
Neuvonen
P J
PJ
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004311:Double-Blind Method; D004357:Drug Synergism; D005260:Female; D006207:Half-Life; D006801:Humans; D017964:Itraconazole / Q000009:adverse effects*; D007654:Ketoconazole / Q000009:adverse effects*; D008297:Male; D012016:Reference Values; D014229:Triazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*
D014229:Triazolam; D017964:Itraconazole; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole