What is the metabolism of oxycodone (OxyContin)?

From the Guidelines

Oxycodone is primarily metabolized in the liver through two main pathways, involving the cytochrome P450 enzymes CYP3A4 and CYP2D6, with genetic variations and drug interactions significantly affecting its metabolism and efficacy. The major pathway involves CYP3A4, which converts oxycodone to noroxycodone, a less potent metabolite, while the second pathway uses CYP2D6 to produce oxymorphone, which has higher analgesic potency than the parent drug 1.

Metabolic Pathways

• CYP3A4: converts oxycodone to noroxycodone
• CYP2D6: converts oxycodone to oxymorphone Genetic variations in these enzymes, such as CYP2D6 "ultra-rapid metabolizers" or "poor metabolizers", can significantly affect how individuals respond to oxycodone, with ultra-rapid metabolizers potentially experiencing enhanced effects or toxicity, and poor metabolizers having reduced pain relief 1.

Drug Interactions

Medications that inhibit CYP3A4 (like erythromycin, ketoconazole, or grapefruit juice) or CYP2D6 (such as fluoxetine or paroxetine) can increase oxycodone blood levels and potentially cause overdose, while enzyme inducers like rifampin or St. John's wort may decrease effectiveness 1.

Elimination

Oxycodone and its metabolites are primarily eliminated through the kidneys, with approximately 10% excreted unchanged in urine, and patients with liver or kidney impairment typically require dose adjustments to prevent accumulation and toxicity, as noted in a recent guideline for the use of opioids in adults with pain from cancer or cancer treatment 1.

Clinical Considerations

In patients with significant renal function impairment, the use of opioids like oxycodone may require caution and dose adjustments to prevent accumulation of active metabolites and opioid-induced neurotoxicity, and alternative opioids like hydromorphone or fentanyl may be preferred 1. Additionally, the use of opioids in patients with liver impairment should take into account the preferential metabolic pathway and active metabolites of the opioid, with lower doses and cautious titration recommended 1. Therefore, it is essential to carefully evaluate the metabolic pathways and potential drug interactions of oxycodone in individual patients, particularly those with liver or kidney impairment, to ensure safe and effective use.

From the FDA Drug Label

Metabolism A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism, and is catalyzed by CYP3A4. Oxymorphone is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6 [see Drug Interactions (7)] Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. The major circulating metabolite is noroxycodone with an AUC ratio of 0. 6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations.

The metabolism of oxycodone involves:

• N-dealkylation to noroxycodone, catalyzed by CYP3A4
• O-demethylation to oxymorphone, catalyzed by CYP2D6 The major circulating metabolite is noroxycodone, with an AUC ratio of 0.6 relative to oxycodone 2

From the Research

Metabolism of Oxycodone

• Oxycodone is primarily metabolized in the liver by the cytochrome P450 (CYP) enzymes, with CYP3A as the major metabolic pathway and CYP2D6 as the minor metabolic pathway to noroxycodone, oxymorphone, and noroxymorphone 3.
• The two main metabolites of oxycodone are oxymorphone, which is also a potent analgesic, and noroxycodone, a weak analgesic 4.
• Oxycodone metabolism is more predictable than that of morphine, and therefore titration is easier 4.
• The bioavailability of oxycodone is higher than that of morphine and less variable 3.

Enzymes Involved in Oxycodone Metabolism

• CYP3A4 and CYP3A5 display the highest activity for oxycodone N-demethylation, while CYP2D6 has the highest activity for O-demethylation 5.
• CYP3A-mediated noroxycodone formation exhibits a mean K(m) of 600 +/- 119 microM and a V(max) that ranges from 716 to 14523 pmol/mg/min 5.
• Quinidine inhibition shows that CYP2D6 is the high affinity enzyme for O-demethylation with a mean K(m) of 130 +/- 33 microM and a V(max) that ranges from 89 to 356 pmol/mg/min 5.

Factors Affecting Oxycodone Metabolism

• Simultaneous inhibition of both CYP3A and CYP2D6 results in increased oxycodone concentrations, and such a combination should be avoided 3.
• Concomitant use of enzyme inducers such as rifampicin, St John's wort, and carbamazepine should be avoided because of the risk of subtherapeutic concentrations of oxycodone 3.
• The metabolism of CYP2D6 substrates varies to a large degree between individuals as a result of allele functionality, with poor metabolizers (PM) having two non-functional alleles, extensive metabolizers (EM) being homozygous with two functional alleles or heterozygous with one functional allele, and ultrarapid metabolizers (UM) having more than two functional alleles 3.

Prediction of Hepatic Plasma Clearance

• The predicted hepatic plasma clearances of oxycodone were typically much lower than the published median total plasma clearance from pharmacokinetic studies 6.
• A clear correlation between in vitro oxycodone clearance and CYP3A4 activity was observed, suggesting that CYP3A activity is the major determinant in metabolic clearance of oxycodone regardless of age group or individual variability in hepatocyte batches 6.

Physiologically Based Pharmacokinetic Modeling

• A physiologically based pharmacokinetic (PBPK) model was built for oxycodone, two primary metabolites (noroxycodone, oxymorphone), and one secondary metabolite (noroxymorphone) to simulate drug-drug interactions (DDI) 7.
• The model was refined and verified against literature clinical data after oxycodone administration in the absence of DDI, and further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin, and CYP2D6 inhibitor quinidine 7.