Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects.
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Gelston EA, Coller JK, Lopatko OV, James HM, Schmidt H, White JM, Somogyi AA
Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects.
Br J Clin Pharmacol. 2012 May;73(5):786-94. doi: 10.1111/j.1365-2125.2011.04145.x.
- PubMed ID
- 22092298 [ View in PubMed]
- Abstract
AIMS: To 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. METHODS: Ten 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. RESULTS: The 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). CONCLUSION: Methadone 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Codeine UDP-glucuronosyltransferase 2B4 Protein Humans UnknownSubstrateDetails Methadone Cytochrome P450 2D6 Protein Humans NoSubstrateInhibitorDetails