Effect of inhibition of cytochrome P450 enzymes 2D6 and 3A4 on the pharmacokinetics of intravenous oxycodone: a randomized, three-phase, crossover, placebo-controlled study.
Author(s): Gronlund J, Saari TI, Hagelberg NM, Neuvonen PJ, Laine K, Olkkola KT
Affiliation(s): Department of Anesthesiology, University of Turku and Turku University Hospital, Turku, Finland. email@example.com
Publication date & source: 2011, Clin Drug Investig., 31(3):143-53.
Publication type: Randomized Controlled Trial; Research Support, Non-U.S. Gov't
BACKGROUND AND OBJECTIVE: Oxycodone is a mu-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. CONCLUSION: 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.