Methadone, metabolism

Besides being affected by medications and substances that affect the liver s metabolism, methadone itself affects the liver s metabolism of certain substances. A significant number of people who are taking methadone for heroin addiction also are HIV positive and are taking anti-HIV medications such as Desipramine (DMI) and zidovudine (AZT). Through its actions on the liver, methadone decreases the metabolism of these medications. Because of this, certain troublesome side effects of DMI and AZT, including nausea,... 

CYP3A4, may contribute to methadone metabolism. Even with adequate methadone plasma levels, some patients continue to abuse drugs, such as sedatives, possibly because they are seeking some form of intoxication rather than relief of opioid hunger (Bell et al. 1990). Relapse to illicit drug use is also common during periods of high stress, even in patients with adequate plasma levels. 

Shi J, Hui L, Xu Y, et al Sequence variations in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Hum Mutat 19 459 60, 2002 Shinderman M, Maxwell S, Brawand-Arney M, etal Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and methadone doses. Drug Alcohol Dependence 69 205-211, 2003... 

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. 

Carbamazepine is an inducer of CYP3A4 and methadone is primarily metabolized via CYP3A4 if carbamazepine is added to a drug regimen containing methadone, the methadone dose will probably need to be adjusted upward to avoid withdrawal. 

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. 

Rifampin Azoles, cyclosporine, methadone propranolol, Pis, oral contraceptives, tacrolimus, warfarin Increased metabolism of other agent Avoid if possible... 

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,... 

Racemic methadone (MET) is administered to heroin addicts as a substitution therapy. However, methadone enantiomers possess different pharmacological effects, and the drug has been demonstrated to be enantioselectively metabolized to its two major metabolites, 2-ethylidene-l,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-l-pyrroline (EMDP). Stereoselective separation of MET, EDDP, and EMDP using an alpha-glycoprotein stationary phase and MS-MS detection was proposed by Kelly et al. [34]. Optimal separation conditions were 20 mM acetic acid isopropanol (93 7, pH 7.4), with a flow rate of 0.9mL/min. 

Nevirapine induces and is metabolized by CYP3A4 therefore, coadministration of drugs that induce or are metabolized by this isoenzyme may result in interactions. Nevirapine may decrease the effectiveness of ethinyl estradiol-based contraceptives and can lower plasma concentrations of methadone. Nevirapine should not be administered with ketoconazole, rifampin, or rifabutin. 

The presence of HIV does not fundamentally affect the direct treatments for drug misuse, but with increasing illness there may be similar issues to those in the older addicts with other physical diseases, which have been discussed. When HIV antiviral therapy is given there may be some reduced efficacy of methadone through increased metabolism (Akerele et al. 2002), but if this seems to be so the dose can readily be increased. As more injecting drug users who became infected despite the preventive measures actually become ill with the disease, it is necessary for workers to have some knowledge of the treatments which are applied. 

Nevirapine is a moderate inducer of CYP3A metabolism, resulting in decreased levels of amprenavir, indinavir, lopinavir, saquinavir, efavirenz, and methadone (Table 49-4). Drugs that induce the CYP3A system, such as tipranavir, rifampin, rifabutin, and St. John s wort, can decrease levels of nevirapine, whereas those that inhibit CYP3A activity, such as fluconazole, ketoconazole, and clarithromycin, can increase nevirapine levels. 

Large individual variations in the urine excretion of methadone are observed depending on urine volume and pH, the dose and rate of metabolism. Acidification of the urine may increase the urinary output of methadone from 5 to 22%.37 Typically, following a 5-mg oral dose, methadone and EDDP account for 5% of the dose in the 24-h urine. In those individuals on maintenance therapy, methadone may account for 5 to 50% of the dose in the 24-h urine and EDDP may account for 3 to 25% of the dose. (S)- and (R)-methadone and EDDP have been reported in saliva38 and methadone and (S)- and (R)-methadone in human breast mi Ik.39 40... 

Since nevirapine is metabolized by the cytochrome P-450 system and induces 3A4 and 2B6, other drugs that are also metabolized by these isoenzymes will have low plasma levels when given in combination. It also increases the clearance of methadone and results in methadone withdrawal. Nevirapine decreases the plasma concentrations of norethindrone, ethinyl estradiol and protease inhibitors (HIV). 

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