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 whethe r such an interaction takes place in vivo following oral administratio n of these drugs, given as relevant double blinded doses in capsule fo rm. In study I parallel groups of healthy subjects received oral midaz olam 10 mg (MLD 10) or 15 mg (MID 15), placebo, or MID 10 mg + 150 mg fluconazole (FLU) given 2 h earlier. Objective and subjective performa nce tests were made before, and 30 and 90 min after the intake of mida zolam. MID 10 and MID 15 moderately impaired performance on digit symb ol substitution,letter cancellation and flicker fusion tests, and visu al analogue scales revealed mild sedation. FLU + MID 10 had similar or slightly stronger effects than MID 10; it differed from MID 10 in tha t it lowered the flicker fusion threshold and produced subjective slow ness and overall impairment. In study II 5 subjects received MID 10 af ter placebo, after FLU, and after 750 mg erythromycin (ERY) at 1-week intervals, following a crossover and double-blinded study design. Bloo d was sampled before MID intake and 30, 60 and 90 min after it, and pe rformance was measured. FLU acid ERY increased the effect of MID on fl icker fusion and letter cancellation performances, and increased the H PLC-assayed plasma midazolam (ERY + 100%, FLU + 50%) in comparison to that measured after MID ingested alone. When the concentrations of mid azolam together with its active metabolite alpha-OH-midazolam were ass ayed by radioreceptor technique the increases caused by ERY and FLU we re less and compatible with the pharmacodynamic data. We conclude that oral 150 mg fluconazole increases the effects of midazolam slightly, hardly to a clinically meaningful extent. The active metabolite of mid azolam may confound the relevance of moderate increases in plasma mida zolam concentrations.