Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
OBJECTIVE
The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone.


METHODS
The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2 mg/kg).


RESULTS
Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above-mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo.


CONCLUSIONS
Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodone.
Kummer
Oliver
O
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital, 4031 Basel, Switzerland.
Hammann
Felix
F
Moser
Claudine
C
Schaller
Olivier
O
Drewe
Jürgen
J
Krähenbühl
Stephan
S
D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018592:Cross-Over Studies; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D005838:Genotype; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D015877:Miosis; D009019:Morphinans / Q000378:metabolism / Q000494:pharmacology; D010098:Oxycodone / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010111:Oxymorphone / Q000378:metabolism / Q000494:pharmacology; D010147:Pain Measurement; D017374:Paroxetine / Q000494:pharmacology; D010919:Placebos; D055815:Young Adult
D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D009019:Morphinans; D010919:Placebos; D017374:Paroxetine; C077256:noroxycodone; D010111:Oxymorphone; D010098:Oxycodone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole