The Effect of Intravenous and Oral Fluconazole on the Pharmacokinetics and Pharmacodynamics of Intravenous Alfentanil

Abstract

The azole antimycotic fluconazole inhibits cytochrome P450 enzymes.We studied the possible interaction of alfentanil with oral and IV fluconazole in a three-phase, double-blind, placebo-controlled, randomized, crossover 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 IV fluconazole 400 mg in saline or saline only. The dose of 20 [micro sign]g/kg of alfentanil was given IV 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 [center dot] min (-1) [center dot] kg-1 to 1.3 +/- 0.3 mL [center dot] min-1 [center dot] kg-1 after IV fluconazole and to 1.4 +/- 0.4 mL [center dot] min-1 [center dot] kg-1 after oral fluconazole (P < 0.001). The mean elimination half-life of alfentanil was almost doubled after both oral and IV fluconazole (P < 0.001). Fluconazole increased the subjective effects of alfentanil as quantified on visual analog scales (P < 0.01). Correspondingly, both IV 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 IV 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 IV. Alfentanil 20 [micro sign]g/kg was given IV 1 h after pretreatment. Fluconazole decreased the clearance of alfentanil by 55% and increased the alfentanil-induced subjective effects.

(Anesth Analg 1998;87:190-4)