Oxymorphone metabolite

Nalbuphine hydrochloride is structurally related to oxymorphone and naloxone. It is approximately equipotent with morphine. Nalbuphine is metabolised in the liver to inactive metabolites. The plasma terminal half-life is approximately 5 h. The onset of analgesia is within 2-3 min of intravenous administration and 15 min after intramuscular injection, and lasts 3-6 h with an adult dose of 10 mg. With equi-analgesic doses, similar degrees of respiratory depression to that of morphine occur up to a dose of approximately 0.45 mg-kg-1. With higher doses a ceiling effect occurs. Sedation, possibly mediated by K-receptor activation, occasionally occurs. The incidence of psychotomimetic side effects is lower than with pentazocine. The abuse potential is low, but is can cause withdrawal symptoms in opioid-dependent subjects. It has occasionally been used to reverse opioid-induced respiratory depression. 

Opioid receptor binding Oxycodone (Chen et al., 1991) is a p-selective opioid with a 10-fold higher receptor affinity than codeine. Both the parent compound and the high affinity metabolite oxymorphone mediate the opioid effects of the compound (Cleary et al., 1994). 

Pharmacokinetic properties Oxycodone (Kaiko et al., 1996) is well absorbed from the gastrointestinal tract. It is metabolized to nor-oxycodone and to a lesser extent to the active metabolite oxymorphone (Poyhia et al., 1993). Metabolites and unchanged parent drug are excreted in the urine. 

Disposition in the Body. Absorbed after oral administration. About 50% of an oral dose is excreted in the urine in 5 days (mostly in the first 24 hours), mainly as conjugated oxymorphone together with small quantities of unchanged drug and the conjugated 6a- and 6 -hydroxy metabolites. 

A number of drugs of abuse are known substrates (e.g., codeine, hydrocodone, p-methoxyamphetamine, amphetamine) or inhibitors (e g., (-)-cocaine, pentazocine) of CYP2D6. For some of these drugs, the pharmacokinetic differences due to the polymorphism will be so profound that they are likely to exceed pharmacodynamic sources of variation in response. For other drugs (e.g., hydrocodone to hydromorphone, codeine to morphine, oxycodone to oxymorphone), CYP2D6 may not contribute importantly to the overall clearance of the drug, but may catalyze the formation of highly active metabolites. 

Quinidine, given as 200 mg 3 hours before and 100 mg 6 hours after a single 20-mg dose of oxycodone almost completely inhibited the formation of the metabolite, oxymorphone in 10 healthy extensive metabolisers of the cytochrome P450 isoenzyme CYP2D6. Despite this, the psychomotor and subjective effects of oxycodone were not altered (note that analgesia was not assessed). The AUC of the metabolite noroxycodone was increased about 85%, and the oxycodone AUC was slightly increased by 13%. Similar results were found in the preliminary report of another study. ... 

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. 

Administration of opioids for chronic arthritic pain in elderly people is effective but can be associated with problematic adverse reactions, particularly morphine and related compounds in those with chronic renal insufficiency [53 ]. There is a higher frequency of nausea, constipation, and cognitive impairment. Pethidine, dextro-propoxyphene, and pentazocine should also be avoided because they have toxic metabolites. Preferred alternatives are hydro-morphone, oxycodone, and oxymorphone. 

Oxymorphone is also produced as a metabolite of oxycodone - the liver metabolises oxycodone by means of 0-demethylation and it is catalysed by cytochrome P450-2D6. 

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... 

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