Metabolism of methadone

Oda, Y., Kharasch, E. D., Metabolism of methadone and levo-a-acetyl-methadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4) potential contribution of intestinal metabolism to presystemic clearance and bioactivation, J. Pharmacol. Exp. Ther. 2001, 298, 1021-1032. 

A comparable reaction was seen decades ago in the metabolism of methadone [173 - 175]. This well-known synthetic opiate undergoes A-demeth-ylation as a major metabolic reaction in humans and laboratory animals. The resulting secondary amine (11.168, Fig. 11.21) has never been isolated, as it undergoes practically instantaneous cyclization. The reaction is believed to proceed via the carbinolamine with formation of metabolite 11.169 as the major urinary metabolite in humans. This structurally intriguing basic compound is, in its neutral form, a pyrrolidine with an exocyclic C=C bond,... 

Methadone is mainly broken down, or metabolized, in the liver. Therefore, any other medications or substances that affect the functioning of the liver can change the rate of metabolism of methadone, either increasing or decreasing the amount in a person s bloodstream. 

Enzyme-inducing drugs, such as carbamazepine, pheno-barbital, phenytoin, and rifampicin, enhance the metabolism of methadone, leading to lower serum methadone concentrations (58). 

OPIOIDS CIPROFLOXACIN 1. Effects of methadone t by ciprofloxacin 2.1 levels of ciprofloxacin with opioids 1. Ciprofloxacin inhibits CYP1A2-, CYP2D6- and CYP3A4-mediated metabolism of methadone 2. Uncertain 1. Watch for t effects of methadone 2. Avoid opioid premedication when ciprofloxacin is used as surgical prophylaxis... 

METHADONE NNRTIs Methadone levels may be significantly 1 by efavirenz and nevirapine t CYP3A4- and 2B6-mediated metabolism of methadone Monitor closely for opioid withdrawal t dose as necessaiy. Likely to need dose titration of methadone (mean 22% but up to 186% t)... 

Ciprofloxacin, given to a patient who had been successfully treated with methadone for more than 6 years, caused profound sedation, confusion, and respiratory depression (73). This may have been due to inhibition of CYP1A2 and CYP3A4, two of the isozymes involved in the metabolism of methadone. 

Side effects, toxicity, and conditions that alter sensitivity, as well as the treatment of acute intoxication, are similar to those described for morphine. During long-term administration, there may be excessive sweating, lymphocytosis, and increased concentrations of prolactin, albumin, and globulins in the plasma. Rifampin and phenytoin accelerate the metabolism of methadone and can precipitate withdrawal symptoms. 

Ketoconazole. An in vitro study suggests that clinically relevant concentrations of ketoconazole decreased the hepatic metabolism of methadone by about 50 to 70%. ... 

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. 

Efavirenz and nevirapine induce the metabolism of methadone (possibly by the cytochrome P450 isoenzyme CYP3A4, or CYP2B6 ), which results in reduced levels and effects. In contrast, delavirdine is an inhibitor... 

Quinidine sulfate 600 mg, given one hour before intravenous methadone hydrochloride 10 mg, did not alter methadone-induced miosis in healthy subjects. However, the same dose of quinidine given before oral methadone hydrochloride 10 mg (with ondansetron as an antiemetic) increased the peak methadone-induced miosis by 34% and increased the plasma levels of oral methadone in the absorption phase, but had no effect on the maximum plasma level or AUC of methadone. Methadone is primarily metabolised by CYP3A and quinidine does not affect the hepatic metabolism of methadone. However, quinidine can inhibit P-glycoprotein and this may affect methadone intestinal transport and absorption. ... 

Rifampicin is a potent enzyme-inducer, which increases the aetivity of the intestinal and liver enzymes concerned with the metabolism of methadone, resulting in a marked decrease in its levels. In 4 patients in the study cited, the urinary excretion of the major metabolite of methadone rose by 150%. Rifabutin has only a small enzyme-indueing effect and therefore the effects are not as great. 

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