title: Effect of inhibition of cytochrome P450 enzymes 2D6 and 3A4 on the pharmacokinetics of intravenous oxycodone: a randomized, three-phase, crossover, placebo-controlled study.
abstract: OBJECTIVE
  Oxycodone is a μ-opioid receptor agonist that is mainly metabolized by hepatic cytochrome P450 (CYP) enzymes. Because CYP enzymes can be inhibited by other drugs, the pharmacokinetics of oxycodone are prone to drug interactions. The aim of this study was to determine whether inhibition of CYP2D6 alone by paroxetine or inhibition of both CYP2D6 and CYP3A4 by a combination of paroxetine and itraconazole alters the pharmacokinetics of and pharmacological response to intravenous oxycodone.
  
  
  METHODS
  We used a randomized, three-phase, crossover, placebo-controlled study design in 12 healthy subjects. The subjects were given 0.1  mg/kg of intravenous oxycodone after pre-treatments with placebo, paroxetine or a combination of paroxetine and itraconazole for 4 days. Plasma concentrations of oxycodone and its oxidative metabolites were measured over 48 hours, and pharmacokinetic and pharmacodynamic parameters subsequently evaluated.
  
  
  RESULTS
  The effect of paroxetine on the plasma concentrations of oxycodone was negligible. The combination of paroxetine and itraconazole prolonged the mean elimination half-life of oxycodone from 3.8 to 6.6 hours (p < 0.001), and increased the exposure to oxycodone 2-fold (p < 0.001). However, these changes were not reflected in pharmacological response.
  
  
  CONCLUSIONS
  The results of this study indicate that there are no clinically relevant drug interactions with intravenous oxycodone and inhibitors of CYP2D6. If both oxidative metabolic pathways via CYP3A4 and 2D6 are inhibited the exposure to intravenous oxycodone increases substantially.
authors.affiliation: Department of Anesthesiology, University of Turku and Turku University Hospital, Turku, Finland. juha.gronlund@utu.fi
authors.forename: Juha
authors.initials: J
authors.lastname: Grönlund
authors.forename: Teijo I
authors.initials: TI
authors.lastname: Saari
authors.forename: Nora M
authors.initials: NM
authors.lastname: Hagelberg
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000145:classification* / Q000494:pharmacology; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D008297:Male; D010098:Oxycodone / Q000493:pharmacokinetics* / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D017964:Itraconazole; D017374:Paroxetine; D010098:Oxycodone; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human