WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Although not well recognized, methadone inhibits CYP2D6 in vivo and in vitro and UGT2B7 and 2B4 in vitro.• We aimed to investigate the effect of methadone on the pathways of codeine metabolism, namely O-demethylation (CYP2D6), 6-glucuronidation (UGT2B4/7) and N-demethylation (CYP3A4/2C8), in subjects maintained on methadone or buprenorphine as a control. WHAT THIS STUDY ADDS• Compared with subjects on buprenorphine, methadone reduced the clearance of codeine to morphine and to codeine-6-glucuronide but had no effect on norcodeine formation.• Plasma morphine concentrations remained unchanged, as although its formation was reduced, its metabolism to M3G and M6G was also reduced.• Metabolic drug interactions with methadone cannot assume substrate-dependent inhibition. 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 Ϯ SD, 2.8 Ϯ 3.1) compared with those taking buprenorphine (0.60 Ϯ 0.43), likewise for 6-glucuronide formation (0.31 Ϯ 0.24 vs. 0.053 Ϯ 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.
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