title: Miconazole oral gel increases exposure to oral oxycodone by inhibition of CYP2D6 and CYP3A4.
abstract: Our aim was to assess the effect of miconazole oral gel on the pharmacokinetics of oral oxycodone. In an open crossover study with two phases, 12 healthy volunteers took a single oral dose of 10 mg of immediate-release oxycodone with or without thrice-daily 85-mg miconazole oral gel treatment. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h. Pharmacological effects of oxycodone were recorded for 12 h. Pharmacokinetic parameters were compared by use of the geometric mean ratios (GMRs) and their 90% confidence interval (CIs). Pretreatment with miconazole oral gel caused a strong inhibition of the CYP2D6-dependent metabolism and moderate inhibition of the CYP3A4-dependent metabolism of oxycodone. The mean area under the concentration-time curve (AUC) from time zero to infinity (AUC(0-∞); GMR, 1.63; 90% CI, 1.48 to 1.79) and the peak concentration of oxycodone (GMR, 1.31; 90% CI, 1.19 to 1.44) were increased. The AUC of the CYP2D6-dependent metabolite oxymorphone was greatly decreased (GMR, 0.17; 90% CI, 0.09 to 0.31) by miconazole gel, whereas that of the CYP3A4-dependent metabolite noroxycodone was increased (GMR, 1.30; 90% CI, 1.15 to 1.47) by miconazole gel. Differences in the pharmacological response to oxycodone between phases were insignificant. Miconazole oral gel increases the exposure to oral oxycodone, but the clinical relevance of the interaction is moderate. Miconazole oral gel produces a rather strong inhibitory effect on CYP2D6, which deserves further study.
authors.affiliation: Department of Anesthesiology, Intensive Care, Emergency Care, and Pain Medicine, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20520 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
authors.initials: N
authors.lastname: Hagelberg
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000627:therapeutic use*; 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; D005260:Female; D006801:Humans; D008297:Male; D008825:Miconazole / Q000627:therapeutic use*; D010098:Oxycodone / Q000008:administration & dosage / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D008825:Miconazole; D010098:Oxycodone; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human