{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:16:44Z","timestamp":1792523804273,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2012,4,5]],"date-time":"2012-04-05T00:00:00Z","timestamp":1333584000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2012,5]]},"abstract":"<jats:sec><jats:label\/><jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Although not well recognized, methadone inhibits CYP2D6<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>and UGT2B7 and 2B4<jats:italic>in vitro<\/jats:italic>.<\/jats:p><jats:p>\u2022\u2003We aimed to investigate the effect of methadone on the pathways of codeine metabolism, namely O\u2010demethylation (CYP2D6), 6\u2010glucuronidation (UGT2B4\/7) and N\u2010demethylation (CYP3A4\/2C8), in subjects maintained on methadone or buprenorphine as a control.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Compared with subjects on buprenorphine, methadone reduced the clearance of codeine to morphine and to codeine\u20106\u2010glucuronide but had no effect on norcodeine formation.<\/jats:p><jats:p>\u2022\u2003Plasma morphine concentrations remained unchanged, as although its formation was reduced, its metabolism to M3G and M6G was also reduced.<\/jats:p><jats:p>\u2022\u2003Metabolic drug interactions with methadone cannot assume substrate\u2010dependent inhibition.<\/jats:p><\/jats:sec><jats:sec><jats:title>AIMS<\/jats:title><jats:p>To compare the O\u2010demethylation (CYP2D6\u2010mediated), N\u2010demethylation (CYP3A4\u2010mediated) and 6\u2010glucuronidation (UGT2B4\/7\u2010mediated) metabolism of codeine between methadone\u2010 and buprenorphine\u2010maintained CYP2D6 extensive metabolizer subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Ten methadone\u2010 and eight buprenorphine\u2010maintained subjects received a single 60\u2003mg dose of codeine phosphate. Blood was collected at 3\u2003h and urine over 6\u2003h and assayed for codeine, norcodeine, morphine, morphine\u20103\u2010 and \u20106\u2010glucuronides and codeine\u20106\u2010glucuronide.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The urinary metabolic ratio for O\u2010demethylation was significantly higher (<jats:italic>P<\/jats:italic>= 0.0044) in the subjects taking methadone (mean \u00b1 SD, 2.8 \u00b1 3.1) compared with those taking buprenorphine (0.60 \u00b1 0.43), likewise for 6\u2010glucuronide formation (0.31 \u00b1 0.24<jats:italic>vs.<\/jats:italic>0.053 \u00b1 0.027;<jats:italic>P<\/jats:italic>&lt; 0.0002), but there was no significant difference (<jats:italic>P<\/jats:italic>= 0.36) in N\u2010demethylation. Similar changes in plasma metabolic ratios were also found. In plasma, compared with those maintained on buprenorphine, the methadone\u2010maintained subjects had increased codeine and norcodeine concentrations (<jats:italic>P<\/jats:italic>&lt; 0.004), similar morphine (<jats:italic>P<\/jats:italic>= 0.72) and lower morphine\u20103\u2010 and \u20106\u2010 and codeine\u20106\u2010glucuronide concentrations (<jats:italic>P<\/jats:italic>&lt; 0.008).<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>Methadone is associated with inhibition of CYP2D6 and UGTs 2B4 and 2B7 reactions<jats:italic>in vivo<\/jats:italic>, 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\u20106\u2010glucuronide (analgesically active) concentrations were substantially reduced. Drug interactions with methadone are likely to include drugs metabolized by various UGTs and CYP2D6.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2125.2011.04145.x","type":"journal-article","created":{"date-parts":[[2011,11,18]],"date-time":"2011-11-18T03:15:15Z","timestamp":1321586115000},"page":"786-794","source":"Crossref","is-referenced-by-count":30,"title":["Methadone inhibits CYP2D6 and UGT2B7\/2B4<i>in vivo<\/i>: a study using codeine in methadone\u2010 and buprenorphine\u2010maintained subjects"],"prefix":"10.1111","volume":"73","author":[{"given":"Eloise A.","family":"Gelston","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet K.","family":"Coller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga V.","family":"Lopatko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather 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