Figure 24.12 • Metabolism of methadone.

racemate, although the opioid activity resides in the R-enan-tiomer (7-50 times more potent than the S-enantiomer). Methadone may only be dispensed for the treatment of opi-oid addiction by a program certified by the Federal Substance Abuse and Mental Health Services Administration. Methadone is a /-receptor agonist with complex and highly variable pharmacokinetic parameters. Bioavailability following oral administration ranges from 36% to 100%. Steady-state volume of distribution ranges between 1.0 to 8.0 L/kg. Methadone is highly bound to plasma a1-acid glycoprotein (85%-90%), and i1/2 elimination ranged between 8 and 59 hours. The wide range in parameters leads to difficulty when trying to switch from one opioid to methadone for either treatment of pain or substance abuse. Methadone doses and administration schedules need to be individualized and closely monitored. The metabolism and elimination of methadone also lead to much interpatient variability and can be effected by genetic CYP levels, drug-drug interactions, and the pH of the urine (Fig. 24.12).90 The major metabolic pathway of methadone metabolism is via N-demethylation to an unstable product that spontaneously cyclizes to form the inactive 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). Initial reports concluded that CYP3A4 was the major isoform responsible for this pathway, but more recent reports indicate that CYP2B6 is primarily responsible for the N-demethylation.91-95

Adverse effects of methadone include all of the standard opioid effects including constricted pupils, respiratory depression, physical dependence, extreme somnolence, coma, cardiac arrest, and death. In addition, QT interval prolongation and torsades de pointes have been reported. The QT interval prolongation reported for methadone was also observed in another diphenylheptane, levomethadyl, or levo-a-acetyl-methadol (LAAM) (Orlaam) that was also used to treat opioid addiction. The severe cardiac-related adverse events resulted in the removal of LAAM from the U.S. market in 2003.

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