Liver codeine metabolism

Pharmacokinetics Variably absorbed from the GI tract. Protein binding low. Metabolized in liver. Primarily excreted in urine as morphineglucuronide con j ugates and unchanged drug—morphine, codeine, papaverine, etc. Unknown if removed by hemodialysis. Half-life 2-3 hr. 

Researchers have determined that dextromethorphan is approximately equal to codeine in cough-sup-pressing ability. Dextromethorphan is rapidly absorbed from the gastrointestinal tract of the body where it is metabolized by the liver and then mostly excreted in the urine. Dextromethorphan begins to exert its effects within 15 to 30 minutes. The duration of the drag s action is about three to six hours. 

TPMT) or the liver (for UGT and CYP2C9). Certain mutations in these isoforms, or gene variants, produce different phenotypes but most important to drug dosing is the poor metabolizer phenotype that results in heightened exposure to either the parent drug or a major metabolite, or reduced exposure to an active metabolite (e.g., morphine from codeine administration). 

After intravenous administration heroin is very quickly metabolized (half-life is about 3 min) into 6-MAM and morphine. The 6-MAM reaches its maximum concentration in 6 min, then transforms itself into morphine, which reaches its peak in 20 min. In the liver and kidneys, deacetylation occurs, but in the liver other reactions also occur N-demethylahon that leads to normorphine, methylation that leads to codeine and conjugation with glucuronic acid. 

Most opiates are subject to significant first-pass metabolism in the liver, and for this reason, parenteral administration is more effective than per os, although the latter is often of longer duration.07 418 At therapeutic plasma levels, about one-third of the drug is bound to plasma protein. Codeine, which has the morphine 3-OH masked, behaves rather differently, and because of a lower first-pass loss, has a significantly greater po efficacy (about two thirds the parental effect). 

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... 

Codeine Quinidine Reduced analgesic effect Reduced liver metabolism of codeine to morphine... 

Court, M.H., Krishnaswamy, S., Hao, Q., Duan, S.X., Patten, C.J., von Moltke, L.L. and Greenblatt, D.J. (2003) Evaluation of 3 -azido-3 deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes specificity and influence of the UGT2B72 polymorphism. Drug Metabolism and Disposition The Biological Fate of Chemicals, 31, 1125—1133. 

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. 

Codeine is chiefly metabolized in the liver where it imdergoes o-demethylation, N-demethylation and partial conjugation with glycuronic acid. It is mostly excreted in the urine as narcodeine and morphine (both as its free and conjugated form). It is found to be less apt than morphine to produce nausea, vomitting, constipation and miosis. It also causes addiction liabilities resulting into enhanced tolerance limits. 

Nagamatsn and coworkers (1985) have reported in vitro formation of codeinone from codeine by rat or gninea pig liver homogenate. Codeinone may be a metabolic intermediate in the presence of nicotinamide adenine dinncleotide (NAD). Its acute toxicity in mice was determined to be 30 times higher than that of codeine. 

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. 

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