title: 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesia and Clinical Pharmacology, University of Helsinki, Finland.
authors.forename: V J
authors.initials: VJ
authors.lastname: Palkama
authors.forename: M H
authors.initials: MH
authors.lastname: Isohanni
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: K T
authors.initials: KT
authors.lastname: Olkkola
mesh_terms: D000284:Administration, Oral; D000328:Adult; D015760:Alfentanil / Q000493:pharmacokinetics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010919:Placebos
chemical_list: D000701:Analgesics, Opioid; D000935:Antifungal Agents; D010919:Placebos; D015760:Alfentanil; D015725:Fluconazole