title: Voriconazole, but not terbinafine, markedly reduces alfentanil clearance and prolongs its half-life.
abstract: OBJECTIVE
  Alfentanil is a short-acting synthetic opioid analgesic, which is extensively metabolized, mainly by hepatic cytochrome P450 (CYP) 3A enzymes. Concomitant administration of alfentanil and CYP3A inhibitors may lead to clinically important drug interactions. We investigated the possible interactions between alfentanil and orally administered voriconazole and terbinafine.
  
  
  METHODS
  A randomized crossover study design in 3 phases was used. Twelve healthy volunteers were given 20 microg/kg intravenous alfentanil without pretreatment (control), after oral voriconazole administration (400 mg twice on the first day and 200 mg twice on the second day), or after oral terbinafine administration (250 mg once daily for 3 days). Plasma concentrations of alfentanil were measured for 10 hours, and the pharmacokinetic parameters were calculated by use of noncompartmental methods.
  
  
  RESULTS
  Voriconazole decreased the mean plasma clearance of intravenous alfentanil by 85%, from the control value of 4.4+/-2.4 mL.min-1.kg-1 to 0.67+/-0.27 mL.min-1.kg-1 (P<.001), and prolonged its elimination half-life from 1.5+/-0.49 hours to 6.6+/-1.8 hours (P<.001). The area under the alfentanil plasma concentration-time curve was increased by 6-fold by voriconazole (P<.001). Terbinafine had no statistically significant effect on the pharmacokinetics of alfentanil. Alfentanil administration caused nausea in 5 volunteers and vomiting in 2. These side effects all occurred in volunteers in the voriconazole phase.
  
  
  CONCLUSIONS
  Oral voriconazole, but not terbinafine, markedly inhibited the metabolism of alfentanil. Caution should be exercised when alfentanil is given to patients receiving voriconazole. It is reasonable to assume that patients receiving voriconazole require 70% to 90% less alfentanil for the maintenance of analgesia than patients who are not receiving concomitant CYP3A inhibitors.
authors.affiliation: Department of Anesthesiology and Intensive Care, University of Turku, Turku, Finland. teijo.saari@tyks.fi
authors.forename: Teijo I
authors.initials: TI
authors.lastname: Saari
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
authors.forename: Kari
authors.initials: K
authors.lastname: Leino
authors.forename: Mika
authors.initials: M
authors.lastname: Valtonen
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
mesh_terms: D000284:Administration, Oral; D000328:Adult; D015760:Alfentanil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D019540:Area Under Curve; D003117:Color Vision Defects / Q000139:chemically induced; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D020795:Photophobia / Q000139:chemically induced; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012737:Sex Factors; D000077291:Terbinafine; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D014839:Vomiting / Q000139:chemically induced; D065819:Voriconazole
chemical_list: D000701:Analgesics, Opioid; D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011743:Pyrimidines; D014230:Triazoles; D015760:Alfentanil; D000077291:Terbinafine; D065819:Voriconazole