Exposure to oral oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 alone.
BACKGROUND
Oxycodone is an opioid analgesic that is metabolized mainly in the liver by cytochrome P450 (CYP) 2D6 and 3A4 enzymes. So far, the effects of CYP2D6 or CYP3A4 inhibitors on the pharmacokinetics of oxycodone in humans have not been systematically studied.


CONCLUSIONS
Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone. When both of CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially.


OBJECTIVE
The aim of this study was to find out whether the inhibition of cytochrome P450 2D6 (CYP2D6) with paroxetine or concomitant inhibition of CYP2D6 and CYP3A4 with paroxetine and itraconazole, altered the pharmacokinetics and pharmacological response of orally administered oxycodone.


METHODS
A randomized placebo-controlled cross-over study design with three phases was used. Eleven healthy subjects ingested 10 mg of oral immediate release oxycodone on the fourth day of pre-treatment with either placebo, paroxetine (20 mg once daily) or paroxetine (20 mg once daily) and itraconazole (200 mg once daily) for 5 days. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacological (analgesic and behavioural) effects were evaluated.


RESULTS
Paroxetine alone reduced the area under concentration-time curve (AUC(0,0-48 h)) of the CYP2D6 dependent metabolite oxymorphone by 44% (P < 0.05), but had no significant effects on the plasma concentrations of oxycodone or its pharmacological effects when compared with the placebo phase. When both oxidative pathways of the metabolism of oxycodone were inhibited with paroxetine and itraconazole, the mean AUC(0,infinity) of oxycodone increased by 2.9-fold (P < 0.001), and its C(max) by 1.8-fold (P < 0.001). Visual analogue scores for subjective drug effects, drowsiness and deterioration of performance were slightly increased (P < 0.05) after paroxetine + itraconazole pre-treatment when compared with placebo.


CONCLUSIONS
Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone if the function of the CYP3A4 pathway is normal. When both CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially.
Grönlund
Juha
J
Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, Turku, Finland. juha.gronlund@utu.fi
Saari
Teijo I
TI
Hagelberg
Nora M
NM
Neuvonen
Pertti J
PJ
Olkkola
Klaus T
KT
Laine
Kari
K
D000328:Adult; D018592:Cross-Over Studies; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D004347:Drug Interactions; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D010098:Oxycodone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D017374:Paroxetine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D017964:Itraconazole; D017374:Paroxetine; D010098:Oxycodone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human