EFFECT OF ROUTE OF ADMINISTRATION OF FLUCONAZOLE ON THE INTERACTION BETWEEN FLUCONAZOLE AND MIDAZOLAM

Objective: Midazolam is a short-acting benzodiazepine hypnotic extensi vely metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazola m during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharm acodynamics of orally ingested midazolam. Methods: A double-dummy, ran domized, cross-over study in three phases was performed in 9 healthy v olunteers. The subjects were given orally fluconazole 400 mg and intra venously saline within 60 min; orally placebo and intravenously flucon azole 400 mg; and orally placebo and intravenously saline. An oral dos e of 7.5 mg midazolam was ingested 60 min after oral intake of flucona zole/placebo, i.e. at the end of the corresponding infusion. Plasma co ncentrations of midazolam, alpha-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Resu lts: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC(0-3), A UC(0-17)) 2- to 3-fold, the elimination half-life of midazolam 2.5-fol d and its peak concentration (C-max) 2- to 2.5-fold compared with plac ebo. The AUC(0-3) and the C-max of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effect s of midazolam but no differences were detected between the fluconazol e phases. Conclusion: We conclude that the metabolism of orally admini stered midazolam was more strongly inhibited by oral than by intraveno us administration of fluconazole.