Disposition of methadone in methadone maintenance

Area of Science:

• Pharmacology
• Clinical Chemistry
• Addiction Medicine

Background:

• Methadone is a widely used opioid agonist therapy for opioid use disorder.
• Understanding methadone's metabolic pathways and excretion is crucial for optimizing treatment.
• Previous studies have explored methadone pharmacokinetics, but dose-dependent metabolic changes require further investigation.

Purpose of the Study:

• To investigate the metabolic fate of methadone in detoxified opiate addicts.
• To determine if methadone metabolism changes with increasing oral doses.
• To identify and quantify methadone and its metabolites in urine and feces.

Main Methods:

• Six detoxified opiate addicts were administered stepwise increasing doses of methadone (10-80 mg/day) over one month.
• Four subjects received radiolabeled 14C-methadone at the lowest and highest doses.
• Urine and fecal samples were analyzed for methadone and its metabolites using chromatography and mass spectrometry.

Main Results:

• Radioactivity was primarily excreted in urine by two subjects and equally in urine and feces by two others.
• Seven metabolites were identified in urine and three in feces; approximately 75% of these were unconjugated.
• The ratio of metabolites to parent drug increased in 5 of 6 subjects, while urinary recovery of unchanged methadone decreased with higher doses.

Conclusions:

• Oral administration of increasing methadone doses in humans may enhance methadone demethylation.
• Metabolic changes observed suggest dose-dependent alterations in methadone processing.
• These findings contribute to a better understanding of methadone pharmacometabolism in the context of opioid agonist therapy.