150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma midazolam concentrations in healthy subjects.

Fluconazole, an azole antifungal agent, moderately inhibits the CYP3A-mediated metabolism of midazolam in vitro. We therefore studied whether such an interaction takes place in vivo following oral administration of these drugs, given as relevant double blinded doses in capsule form. In study I parallel groups of healthy subjects received oral midazolam 10 mg (MID 10) or 15 mg (MID 15), placebo, or MID 10 mg + 150 mg fluconazole (FLU) given 2 h earlier. Objective and subjective performance tests were made before, and 30 and 90 min after the intake of midazolam. MID 10 and MID 15 moderately impaired performance on digit symbol substitution, letter cancellation and flicker fusion tests, and visual analogue scales revealed mild sedation. FLU + MID 10 had similar or slightly stronger effects than MID 10; it differed from MID 10 in that it lowered the flicker fusion threshold and produced subjective slowness and overall impairment. In study II 5 subjects received MID 10 after placebo, after FLU, and after 750 mg erythromycin (ERY) at 1-week intervals, following a crossover and double-blinded study design. Blood was sampled before MID intake and 30, 60 and 90 min after it, and performance was measured. FLU and ERY increased the effect of MID on flicker fusion and letter cancellation performances, and increased the HPLC-assayed plasma midazolam (ERY + 100%, FLU + 50%) in comparison to that measured after MID ingested alone. When the concentrations of midazolam together with its active metabolite alpha-OH-midazolam were assayed by radioreceptor technique the increases caused by ERY and FLU were less and compatible with the pharmacodynamic data.(ABSTRACT TRUNCATED AT 250 WORDS)