In vitro experiments suggest that circulating metabolites of oxycodoneare opioid receptor agonists.
Clinical and animal studies to date have failed to demonstrate a significant contribution of the O-demethylated
metabolite oxymorphone toward the clinical effects of the parent drug, but the role of other putative circulating
active metabolites in oxycodone pharmacodynamics remains to be examined.
Methods: Pharmacokinetics and pharmacodynamics of oxycodone were investigated in healthy human volunteers;
measurements included the time course of plasma concentrations and urinary excretion of metabolites derived
from N-demethylation, O-demethylation, and 6-keto-reduction, along with the time course of miosis and subjective
opioid side effects. The contribution of circulating metabolites to oxycodone pharmacodynamics was
analyzed by pharmacokinetic-pharmacodynamic modeling. The human study was complemented by in vitro
measurements of opioid receptor binding and activation studies, as well as in vivo studies of the brain distribution
of oxycodone and its metabolites in rats.
Results: Urinary metabolites derived from cytochrome P450 (CYP) 3A–mediatedN-demethylation of oxycodone
(noroxycodone, noroxymorphone, and - and -noroxycodol) accounted for 45%  21% of the dose, whereas
CYP2D6-mediated O-demethylation (oxymorphone and - and -oxymorphol) and 6-keto-reduction (- and
-oxycodol) accounted for 11%6% and 8%6% of the dose, respectively. Noroxycodone and noroxymorphone
were the major metabolites in circulation with elimination half-lives longer than that of oxycodone, but their
uptake into the rat brain was significantly lower compared with that of the parent drug. Pharmacokineticpharmacodynamic
modeling indicated that the time course of pupil constriction is fully explained by the plasma
concentration of the parent drug, oxycodone, alone. The metabolites do not contribute to the central effects,
either because of their low potency or low abundance in circulation or as a result of their poor uptake into the