Metabolism of oxycodone

Poyhia, R., T. Seppala, K.T. Olkkola, and E. Kalso, The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects, Br. J. Clin. Pharmacol., 33(6), 617-621, 1992. 

Figure 34-39 Metabolism of oxycodone and oxymorphone. Values in parentheses are percent of oxycodone dose excreted in urine. For oxymorphone dose, 1.9% is excreted as the parent drug, 44% as conjugates, and 3% as oxymorphoi.

The UK manufacturer of oxycodone suggests that inhibitors of CYP3A enzymes such as ketoconazole may inhibit the metabolism of oxycodone, although oxycodone is also metabolised via CYP2D6. ... 

Fluoxetine inhibits the activity of the cytochrome P450 isoenzyme CYP2D6 within the liver so that the metabolism of oxycodone to an aetive metabolite oxymorphone is reduced. The metabolism of hydroeodone and similar opioids may also be affected by CYP2D6 inhibitors, see Opioids Codeine and related drugs + Quinidine , p.l84. Buprenorphine and morphine are not metabolised by CYP2D6, so their metabolism would not be expeeted to be affected by fluoxetine. Buprenorphine is metabolised by CYP3A4 and so fluvoxamine might be expected to inhibit its metabolism to some extent. 

Paroxetine In a randomized, double-blind, placebo-controlled, crossover study of the interaction of oxycodone and paroxetine, a potent inhibitor of CYP2D6, in 20 patients with chronic pain, paroxetine had significant effects on the metabolism of oxycodone but did not significantly alter oxycodone analgesia [156 ]. 

SSRIs OPIOIDS 1. Possible 1 analgesic effect of oxycodone and tramadol 2. T serotonin effects, including possible cases of serotonin syndrome, when opioids (oxycodone, pethidine, pentazocine, tramadol) are co-administered with SSRIs (fluoxetine and sertraline) 3. SSRIs may t codeine, fentanyl, methadone, pethidine and tramadol levels 1. Uncertain. Paroxetine inhibits CYP2D6, which is required to produce the active form of tramadol. 2. Uncertain 3. SSRIs inhibit CYP2D6-mediated metabolism of these opioids 1. Consider using an alternative opioid 2. Look for signs of T serotonin activity, particularly on initiating therapy 3. Watch for excessive narcotization... 

IMATINIB ANALGESICS-OPIOIDS May cause t plasma concentrations, with a risk of toxic effects of codeine, dextromethorphan, hydroxycodone, methadone, morphine, oxycodone, pethidine and tramadol Inhibition of CYP2D6-mediated metabolism of these opioids Monitor for clinical efficacy and toxicity. Warn patients to report t drowsiness, malaise or anorexia. Measure amylase and lipase levels if toxicity is suspected. Tramadol causes less respiratory depression than other opiates, but need to monitor BP and blood counts, and advise patients to report wheezing, loss of appetite and fainting attacks. Need to consider 1 dose. Methadone may cause Q-T prolongation the CHM has recommended that patients with heart and liver disease who are on methadone should be carefully monitored for heart conduction abnormalities such as Q-T prolongation on ECG as they may lead to sudden death. Also need to monitor patients on more than 100 mg methadone daily and thus an t in plasma concentrations necessitates close monitoring of cardiac and respiratory function... 

Lurcott G. The effects of the genetic absence and inhibition of CYP2D6 on the metabolism of codeine and its derivatives hydrocodone and oxycodone. Anesth Prog 1999 45 154-6. 

Several of the opioids (buprenorphine, hydromorphone, methadone) are metabolised by CYP3A, at least in part, and their metabolism is expected to be reduced by the azoles, which, to varying extents, inhibit CYP3A4. This has been seen when fluconazole and voriconazole are given with methadone, and when ketocona-zole is given with buprenorphine. It has been suggested that keto-conazole inhibits the metabolism of morphine and oxycodone, but evidence for this is sparse. 

An isolated report describes a marked increase in the effects of dextromoramide, resulting in coma, in a man treated with trole-andomycin. Macrolides including troleandomycin and erythromycin are predicted to increase buprenorphine bioavailability. Similarly, the metabolism of hydromorphone is reduced by troleandomycin in vitro. Some manufacturers have su ested that the metabolism of methadone and oxycodone may be decreased by these macrolides, but there do not appear to be any clinical reports confirming this. 

Rifampicin markedly increases the metabolism of codeine and morphine, and reduces their effects. Rifampicin dramatically reduced the effects of oxycodone in one patient. 

Oxycodone is extensively metabolized and eliminated primarily in the urine as both conjugated and unconjugated metabolites. The apparent elimination half-life of oxycodone following the administration of OxyContin was 4.5 hours compared to 3.2 hours for immediate-release oxycodone. About 60% to 87% of an oral dose of oxycodone reaches the central compartment in comparison to a parenteral dose. This high oral bioavailability is due to low pre systemic and/or first-pass metabolism. 

Oxycodone Oxycodone is metabolized maiiily in the hver by CYP3A and CYP2D6, which rifampicin induces. The interaction of rifampicin 600 mg/day for 7 days with a single dose of oxycodone, 0.1 mg/kg intravenously or 15 mg orally, has been studied in a four-session, paired, placebo-controlled crossover study in 12 volunteers [86 ]. Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were determined for 48 hours. Psychomotor... 

Codeine, hydrocodone, morphine, methadone, and oxycodone are substrates of the cytochrome P-450 isoenzyme CYP2D6.47 Inhibition of CYP2D6 results in decreased analgesia of codeine and hydrocodone due to decreased conversion to the active metabolites (e.g., morphine and hydromorphone, respectively) and increased effects of morphine, methadone, and oxycodone. Methadone is also a substrate of CYP3A4, and its metabolism is increased by phenytoin and decreased by cimetidine. CNS depressants may potentiate the sedative effects of opiates. 

Most opioid analgesics are well absorbed when given by subcutaneous, intramuscular, and oral routes. However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) may need to be much higher than the parenteral dose to elicit a therapeutic effect. Considerable interpatient variability exists in first-pass opioid metabolism, making prediction of an effective oral dose difficult. Certain analgesics such as codeine and oxycodone are effective orally because they have... 

Naltrexone (162), like naloxone, was more extensively metabolized after oral adminstration than following the parenteral route. Major metabolites in plasma, urine, and feces have been identified 459 by gc/ms as naltrexone-3-glucuronide and conjugated and unconjugated 6/3-hydroxy reduction product (270). The geometry at C-6 had been established during an earlier study. 460 Minor quantities of the C-2 oxidation product, 270, (R = OMe R = OH) and 270 (R = OMe, R = H) were also found. Oxycodone (44) gave the unusual 6/3,7/3-dihydroxy metabolite (271) in rabbits. 

Initiate therapy of these drugs, particularly those with a narrow therapeutic index, at the lowest effective dose. Interaction is likely to be important with substrates for which CYP2D6 is considered the only metabolic pathway (e.g. hydrocodone, oxycodone, desipramine, paroxetine, chlorpheniramine, mesoridazine, alprenolol, amphetamines, atomoxetine)... 

Oral transmucosal fentanyl citrate has two advantages it is more acceptable as a flavored lozenge than an oral elixir or tablet would be, especially in children, and 25% goes directly into the systemic circulation without first-pass metabolism (SEDA-20, 77). Its main adverse effect is dose-dependent nausea and/or vomiting, which occurs in 25-50% of patients. In a double-blind, placebo-controlled comparison of oral transmucosal fentanyl citrate (10 pg/kg) and oral oxycodone (0.2 mg/kg) in outpatient wound care procedures in 22 children, there were similar outcomes and no adverse effects in either group (40). 

CODEINE In contrast to morphine, codeine is -60% as effective orally as parenteraUy as an analgesic and as a respiratory depressant. Codeine analogs such as levorphanol, oxycodone, and methadone have a high ratio of oral-to-parenteral potency. The greater oral efficacy of these drugs reflects lower first-pass metabolism. Once absorbed, codeine is metaboUzed by the liver, and its metabolites are excreted chiefly as inactive forms in the urine. A relatively small fraction (-10%) of administered codeine is O-demethylated to morphine, and free and conjugated morphine can be found in the urine after therapeutic doses of codeine. Codeine has an exceptionally low affinity for opioid receptors, and the analgesic effect of codeine is due to its conversion to morphine. However, its antitussive actions may involve distinct receptors that bind codeine itself. The tj of codeine in plasma is 2-4 hours. 

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