Is OxyContin (oxycodone) and Roxicodone (oxycodone) primarily metabolized by the liver or kidney?

Metabolism of OxyContin and Roxicodone (Oxycodone)

OxyContin and Roxicodone (both containing oxycodone) are primarily metabolized by the liver, with metabolites and a small amount of unchanged drug excreted by the kidneys. 1

Hepatic Metabolism of Oxycodone

Oxycodone undergoes extensive hepatic metabolism through two main pathways:

1. Primary Pathway: N-demethylation to noroxycodone, catalyzed by CYP3A4 enzyme

   • Noroxycodone is the major circulating metabolite with weak analgesic properties
   • Has an AUC ratio of 0.6 relative to oxycodone 1

2. Secondary Pathway: O-demethylation to oxymorphone, catalyzed by CYP2D6 enzyme

   • Oxymorphone is present in plasma in low concentrations but is a potent analgesic 1, 2

The liver's role in oxycodone metabolism is significant, with the drug having:

• Oral bioavailability of 60-87% due to first-pass metabolism 1, 2
• Plasma half-life of 3.5-4 hours for immediate-release formulations 1
• Plasma protein binding of approximately 45% 1, 2

Renal Excretion

After hepatic metabolism, oxycodone and its metabolites are primarily excreted via the kidneys in the following forms 1:

• Free oxycodone: up to 19%
• Conjugated oxycodone: up to 50%
• Free oxymorphone: 0%
• Conjugated oxymorphone: ≤14%
• Both free and conjugated noroxycodone: present but not quantified

Clinical Implications for Special Populations

Hepatic Impairment

• Oxycodone clearance decreases in patients with hepatic impairment 1, 3
• In liver cirrhosis, oxycodone has:
  • Decreased intrinsic hepatic clearance
  • Longer half-life and lower clearance
  • Greater potency for respiratory depression 3
• The European Association for the Study of the Liver (EASL) recommends avoiding oxycodone in patients with end-stage liver disease 3

Renal Impairment

• Oxycodone is substantially excreted by the kidneys 1
• For patients with renal impairment:
  • Careful titration and frequent monitoring are required 3
  • Consider alternative opioids like methadone (fecally excreted) 3
  • Morphine, meperidine, codeine, and tramadol should be avoided 3

Practical Dosing Considerations

For patients with organ dysfunction:

• Hepatic impairment: Initiate therapy with lower than usual dosage and titrate carefully 1
• Renal impairment: Start with lower doses and monitor closely for adverse events 1
• Elderly patients: Use caution when selecting dosage, usually starting at the low end of the dosing range 1

Comparison to Other Opioids

• Morphine: Primarily metabolized by glucuronidation in the liver with >90% excreted via kidneys 3, 4
• Hydromorphone: Metabolized and excreted by conjugation; half-life remains stable even in liver dysfunction 3
• Fentanyl: Metabolized by cytochromes but doesn't produce toxic metabolites; blood concentration remains unchanged in liver cirrhosis and is not dependent on renal function 3

In conclusion, understanding oxycodone's hepatic metabolism and renal excretion is crucial for safe prescribing, especially in patients with organ dysfunction where dose adjustments may be necessary to prevent adverse effects.