Oxycodone
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🧬 Receptor activity
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Mu-type opioid receptor | — | Ki 8.9 nM | CHEMBL | TargetMu-type opioid receptor Action— AffinityKi 8.9 nM SourceCHEMBL |
| Kappa-type opioid receptor | — | Ki 325 nM | CHEMBL | TargetKappa-type opioid receptor Action— AffinityKi 325 nM SourceCHEMBL |
| Delta-type opioid receptor | — | Ki 487 nM | CHEMBL | TargetDelta-type opioid receptor Action— AffinityKi 487 nM SourceCHEMBL |
| Sigma non-opioid intracellular receptor 1 | — | Ki 10000 nM | CHEMBL | TargetSigma non-opioid intracellular receptor 1 Action— AffinityKi 10000 nM SourceCHEMBL |
| Cannabinoid receptor | — | Ki 10000 nM | CHEMBL | TargetCannabinoid receptor Action— AffinityKi 10000 nM SourceCHEMBL |
Mechanism of action
The full mechanism of oxycodone is not known. Under conditions of inflammation or hyperalgesia, opioid receptors in the heart, lungs, liver, gastrointestinal tract, and reproductive system are upregulated and transported to nerve terminals. Oxycodone and its active metabolites, noroxycodone, oxymorphone, and noroxymorphone are opioid agonists. These compounds passively diffuse across the blood brain barrier or may be actively transported across by an unknown mechanism. Oxycodone and its active metabolites can selectively bind to the mu opioid receptor, but also the kappa and delta opioid receptors in the central nervous system and periphery, and induce a G protein coupled receptor signalling pathway. Activation of mu opioid receptors inhibits N-type voltage operated calcium channels, inhibiting responses to pain.
Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
... Oxycodone has the same mechanism of action as other opioids: binding to a receptor, inhibition of adenylyl-cyclase and hyperpolarization of neurons, and decreased excitability. These mechanisms also play a part in the onset of dependence and tolerance. ...
Pharmacodynamics
Oxycodone acts directly on a number of tissues not related to its analgesic effect. These tissues include the respiratory centre in the brain stem, the cough centre in the medulla, muscles of the pupils, gastrointestinal tract, cardiovascular system, endocrine system, and immune system. Oxycodone's effect on the respiratory centre is dose dependant respiratory depression. The action on the cough centre is suppression of the cough reflex. Pupils become miopic or decrease in size, peristalsis of the gastrointestinal tract slows, and muscle tone in the colon may increase causing constipation. In the cardiovascular system histamine may be released leading to pruritis, red eyes, flushing, sweating, and decreased blood pressure. Endocrine effects may include increased prolactin, decreased cortisol, and decreased testosterone. It is not yet known if the effects of opioids on the immune system are clinically significant.
Pharmacokinetics
Half-life
The apparent elimination half life of oxycodone is 3.2 hours for immediate release formulations and 4.5 hours for extended release formulations. Noroxycodone has a half life of 5.8 hours, oxymorphone has a half life of 8.8 hours, noroxymorphone has a half life of 9 hours.
This study aimed to characterize the pharmacokinetics of oxycodone and its major metabolites in infants and covered the age range between extremely preterm neonates and 2-year-old infants. Seventy-nine infants (gestational age 23-42 weeks; postnatal age 0-650 days) received intravenous oxycodone hydrochloride trihydrate at a dose of 0.1 mg/kg during or after surgery. ... In extremely preterm neonates (n = 6) median of elimination half-life was 8.8 hr (range 6.8-12.5), in preterm (n = 11) 7.4 hr (4.2-11.6), and in older neonates (n = 22) 4.1 hr (2.4-5.8), all of which were significantly longer than that in infants aged 6-24 months (n = 12) 2.0 hr (1.7-2.6). ...
The apparent elimination half-life following oral administration of the extended-release tablets or conventional preparations is 4.5 or 3.2 hours, respectively.
The apparent elimination half-life following oral administration of the extended-release capsules under fed conditions is 5.6 hours, compared with 3.2 hours following administration of conventional preparations of the drug.
The apparent elimination half-life of oxycodone following oral administration of the fixed-combination extended-release tablets is 4.5 hours, compared with 3.9 hours following administration of conventional preparations of the drug.
For more Biological Half-Life (Complete) data for Oxycodone (6 total), please visit the HSDB record page.
Absorption
Oxycodone has an oral bioavailability of 60% to 87% that is unaffected by food. The area under the curve is 135ng/mL\*hr, maximum plasma concentration is 11.5ng/mL, and time to maximum concentration is 5.11hr in patients given a 10mg oral immediate release dose of oxycodone.
Oxycodone and its metabolites are eliminated in the urine. Unbound noroxycodone makes up 23% of the dose recovered in urine and oxymorphone makes up <1%. Conjugated oxymorphone makes up 10% of the recovered dose. Free and conjugated oxycodone makes up 8.9% of the recovered dose, noroxymorphone makes up 14%, and reduced metabolites make up 18%.
2.6L/kg.
Total plasma clearance is 1.4L/min in adults.
About 60 to 87% of an oral dose reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone.
The oral bioavailability of oxycodone is 60-87%. The relative oral bioavailability of extended-release tablets of oxycodone hydrochloride compared with conventional oral preparations is 100%. The extended-release tablets are formulated to provide controlled delivery of oxycodone over 12 hours. Release of the drug from the extended-release tablets is pH independent. Following rectal administration of oxycodone hydrochloride extended-release tablets in healthy adults, the area under the plasma concentration-time curve (AUC) and peak plasma concentration were increased by 39 and 9%, respectively, compared with oral administration. With multiple oral dosing, steady-state plasma concentrations usually are achieved within 24-36 hours in healthy individuals receiving extended-release tablets of oxycodone hydrochloride. Administration of the extended-release tablets with food does not substantially affect the extent of absorption.
Metabolism
Oxycodone's hepatic metabolism is extensive and completed by 4 main reactions. CYP3A4 and 3A5 perform N-demethylation, CYP2D6 performs O-demethylation, unknown enzymes perform 6-keto-reduction, and unknown enzymes perform conjugation. Oxycodone is metabolized by CYP3A4 and CYP3A5 to noroxycodone and then by CYP2D6 to noroxymorphone. Noroxycodone and noroxymorphone are the primary circulating metabolites. Noroxycodone can also be 6-keto-reduced to alpha or beta noroxycodol. Oxycodone can be metabolized by CYP2D6 to oxymorphone and then by CYP3A4 to noroxymorphone. Oxymorphone can also be 6-keto-reduced to alpha or beta oxymorphol. Oxycodone can also be 6-keto-reduced to alpha and beta oxycodol. The active metabolites noroxycodone, oxymorphone, and noroxymorphone can all be conjugated before elimination.
The hepatic metabolism of oxycodone by cytochromes P450 (CYP) and the UDP-glucuronosyltransferases (UGT), the main metabolic enzymes of phase I and phase II, respectively, was assessed in vitro. The N-demethylation by CYP3A4/5 and the O-demethylation by CYP2D6 in human liver microsomes (HLM) followed Michaelis-Menten kinetics, with intrinsic clearances of 1.46 uL/min/mg and 0.35 uL/min/mg, respectively. Although noroxycodone and oxymorphone mainly contribute to the elimination of oxycodone, the simulated total in vivo clearance using in vitro phase I metabolism was underestimated. For the first time, metabolism of oxycodone by UGT was deeply investigated using HLM, recombinant enzymes and selective inhibitors. Oxycodone-glucuronide was mainly produced by UGT2B7 (Km=762 +/- 153 uM, Vmax=344 +/- 20 peak area/min/mg) and to a lesser extent by UGT2B4 (Km=2454 +/- 497 uM, Vmax=201 +/- 19 peak area/min/mg). Finally, the kinetics of the drug-drug interactions were assessed using two CYP and UGT cocktail approaches. Incubations of HLM with phase I and phase II drug probes showed that oxycodone mainly decreased the in vitro activities of CYP2D6, CYP3A4/5, UGT1A3, UGT1A6 and UGT2B subfamily with an important impact on UGT2B7.
Oxycodone hydrochloride is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known.
... The two main metabolites /of oxycodone/ are oxymorphone-which is also a very potent analgesic-and noroxycodone, a weak analgesic. ...
Oxycodone undergoes N-demethylation to noroxycodone and O-demethylation to oxymorphone. The cytochrome P450 (P450) isoforms capable of mediating the oxidation of oxycodone to oxymorphone and noroxycodone were identified using a panel of recombinant human P450s. CYP3A4 and CYP3A5 displayed the highest activity for oxycodone N-demethylation; intrinsic clearance for CYP3A5 was slightly higher than that for CYP3A4. CYP2D6 had the highest activity for O-demethylation. Multienzyme, Michaelis-Menten kinetics were observed for both oxidative reactions in microsomes prepared from five human livers. Inhibition with ketoconazole showed that CYP3A is the high affinity enzyme for oxycodone N-demethylation; ketoconazole inhibited >90% of noroxycodone formation at low substrate concentrations. CYP3A-mediated noroxycodone formation exhibited a mean K(m) of 600 +/- 119 uM and a V(max) that ranged from 716 to 14523 pmol/mg/min. Contribution from the low affinity enzyme(s) did not exceed 8% of total intrinsic clearance for N-demethylation. Quinidine inhibition showed that CYP2D6 is the high affinity enzyme for O-demethylation with a mean K(m) of 130 +/- 33 uM and a V(max) that ranged from 89 to 356 pmol/mg/min. Activity of the low affinity enzyme(s) accounted for 10 to 26% of total intrinsic clearance for O-demethylation. On average, the total intrinsic clearance for noroxycodone formation was 8 times greater than that for oxymorphone formation across the five liver microsomal preparations (10.5 uL/min/mg versus 1.5 uL/min/mg). Experiments with human intestinal mucosal microsomes indicated lower N-demethylation activity (20-50%) compared with liver microsomes and negligible O-demethylation activity, which predict a minimal contribution of intestinal mucosa in the first-pass oxidative metabolism of oxycodone.
Oxycodone has known human metabolites that include oxymorphone and noroxycodone.
Protein binding
45%. Oxycodone is primarily bound to serum albumin and to a lesser degree alpha1-acid glycoprotein.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.