title: Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Eloise A
authors.initials: EA
authors.lastname: Gelston
authors.forename: Janet K
authors.initials: JK
authors.lastname: Coller
authors.forename: Olga V
authors.initials: OV
authors.lastname: Lopatko
authors.forename: Heather M
authors.initials: HM
authors.lastname: James
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Jason M
authors.initials: JM
authors.lastname: White
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
mesh_terms: D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000494:pharmacology*; D002047:Buprenorphine / Q000494:pharmacology*; D003061:Codeine / Q000493:pharmacokinetics*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008691:Methadone / Q000494:pharmacology*; D008875:Middle Aged; D013223:Statistics as Topic; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D002047:Buprenorphine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C486404:UGT2B4 protein, human; D008691:Methadone; D003061:Codeine
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