THE EFFECT OF INTRAVENOUS AND ORAL FLUCONAZOLE ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVENOUS ALFENTANIL

The azole antimycotic fluconazole inhibits cytochrome P450 enzymes. We studied the possible interaction of alfentanil with oral and TV fluco nazole in a three-phase, double-blind, placebo-controlled, randomized, crossover study at intervals of 4 wk. Nine healthy volunteers were gi ven a single oral dose of either fluconazole 400 mg or placebo, follow ed within 60 min by either IV fluconazole 400 mg in saline or saline o nly. The dose of 20 mu g/kg of alfentanil was given IV 1 h after the f luconazole/placebo. Venous plasma samples were collected, and pharmaco dynamic 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 IV fluconazole and to 1.4 +/- 0.4 mL.min(-1).kg(-1) aft er oral fluconazole (P < 0.001). The mean elimination half-life of alf entanil was almost doubled after both oral and TV fluconazole (P < 0.0 01). Fluconazole increased the subjective effects of alfentanil as qua ntified on visual analog scales (P < 0.01). Correspondingly, both IV a nd oral fluconazole also increased the alfentanil-induced respiratory depression by decreasing the respiratory rate by 10%-15% (P < 0.05). W e conclude that metabolism of alfentanil is inhibited by oral and IV f luconazole and that caution should be exercised when alfentanil is giv en to patients receiving fluconazole. Implications: We studied the int eraction of cytochrome P450 3A4 enzyme inhibitor fluconazole with alfe ntanil. Nine volunteers were given placebo or fluconazole 400 mg orall y or TV. Alfentanil 20 mu g/kg was given TV 1 h after pretreatment. Fl uconazole decreased the clearance of alfentanil by 55% and increased t he alfentanil-induced subjective effects.