• Br J Clin Pharmacol · May 2012

    Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects.

    • Eloise A Gelston, Janet K Coller, Olga V Lopatko, Heather M James, Helmut Schmidt, Jason M White, and Andrew A Somogyi.
    • Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, Australia.
    • Br J Clin Pharmacol. 2012 May 1; 73 (5): 786-94.

    AimsTo compare the O-demethylation (CYP2D6-mediated), N-demethylation (CYP3A4-mediated) and 6-glucuronidation (UGT2B4/7-mediated) metabolism of codeine between methadone- and buprenorphine-maintained CYP2D6 extensive metabolizer subjects.MethodsTen methadone- and eight buprenorphine-maintained subjects received a single 60 mg dose of codeine phosphate. Blood was collected at 3 h and urine over 6 h and assayed for codeine, norcodeine, morphine, morphine-3- and -6-glucuronides and codeine-6-glucuronide.ResultsThe urinary metabolic ratio for O-demethylation was significantly higher (P= 0.0044) in the subjects taking methadone (mean ± SD, 2.8 ± 3.1) compared with those taking buprenorphine (0.60 ± 0.43), likewise for 6-glucuronide formation (0.31 ± 0.24 vs. 0.053 ± 0.027; P < 0.0002), but there was no significant difference (P= 0.36) in N-demethylation. Similar changes in plasma metabolic ratios were also found. In plasma, compared with those maintained on buprenorphine, the methadone-maintained subjects had increased codeine and norcodeine concentrations (P < 0.004), similar morphine (P= 0.72) and lower morphine-3- and -6- and codeine-6-glucuronide concentrations (P < 0.008).ConclusionMethadone is associated with inhibition of CYP2D6 and UGTs 2B4 and 2B7 reactions in vivo, even though it is not a substrate for these enzymes. Plasma morphine was not altered, owing to the opposing effects of inhibition of both formation and elimination; however, morphine-6-glucuronide (analgesically active) concentrations were substantially reduced. Drug interactions with methadone are likely to include drugs metabolized by various UGTs and CYP2D6.© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

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