The effect of intravenous and oral fluconazole on the pharmacokinetics and pharmacodynamics of intravenous alfentanil.

UNLABELLED: The azole antimycotic fluconazole inhibits cytochrome P450 enzymes. We studied the possible interaction of alfentanil with oral and i.v. fluconazole in a three-phase, double-blind, placebo-controlled, randomized, cross-over study at intervals of 4 wk. Nine healthy volunteers were given a single oral dose of either fluconazole 400 mg or placebo, followed within 60 min by either i.v. fluconazole 400 mg in saline or saline only. The dose of 20 micrograms/kg of alfentanil was given i.v. 1 h after the fluconazole/placebo. Venous plasma samples were collected, and pharmacodynamic measurements were performed for 10 h. Alfentanil clearance was decreased from 3.1 +/- 1.1 mL.min-1.kg-1 to 1.3 +/- 0.3 mL.min-1. kg-1 after i.v. fluconazole and to 1.4 +/- 0.4 mL.min-1. kg-1 after oral fluconazole (P < 0.001). The mean elimination half-life of alfentanil was almost doubled after both oral and i.v. fluconazole (P < 0.001). Fluconazole increased the subjective effects of alfentanil as quantified on visual analog scales (P < 0.01). Correspondingly, both i.v. and oral fluconazole also increased the alfentanil-induced respiratory depression by decreasing the respiratory rate by 10%-15% (P < 0.05). We conclude that metabolism of alfentanil is inhibited by oral and i.v. fluconazole and that caution should be exercised when alfentanil is given to patients receiving fluconazole. IMPLICATIONS: We studied the interaction of cytochrome P450 3A4 enzyme inhibitor fluconazole with alfentanil. Nine volunteers were given placebo or fluconazole 400 mg orally or i.v. Alfentanil 20 micrograms/kg was given i.v. 1 h after pretreatment. Fluconazole decreased the clearance of alfentanil by 55% and increased the alfentanil-induced subjective effects.

RCT Entities:   Population Interventions Outcomes