Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics ofoxycodone

Background: Oxycodone is metabolized in the liver by means of O-demethylati on to form oxymorphone in a reaction catalyzed by the enzyme cytochrome P45 0 2D6 (CYP2D6). This enzyme is expressed as 2 phenotypes (extensive and poo r metabolizers), Several drugs are metabolized by CYP2D6, and clinically re levant drug interactions may occur. The aim of this study was to evaluate t he role of oxymorphone in mediating the opioid effects of oxycodone by mean s of blocking CYP2D6 with quinidine, Methods: Ten healthy extensive metabolizers were administered 20 mg control led-release oxycodone after premedication with placebo or 200 mg quinidine in this randomized, double-blind crossover study. A dose of 100 mg quinidin e was administered 6 hours later. Plasma opioid concentrations, subjective pharmacodynamic ratings, and psychomotor function were assessed for 24 hour s after drug administration. Results: No oxymorphone was detected at any time after quinidine premedicat ion in 8 of 10 subjects. Plasma oxycodone (difference not significant) and noroxycodone (P<.01) concentrations were greater after quinidine pretreatme nt, Prevention of the production of oxymorphone by quinidine did not affect the psychomotor or subjective drug effects of oxycodone, No difference in number of adverse effects was observed after the 2 pretreatments, Conclusions: A significant reduction in plasma oxymorphone levels did not s ubstantially alter the pharmacodynamic effects of oxycodone, Analgesia was nor evaluated because pain was not present.