{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T21:21:24Z","timestamp":1792358484432,"version":"4.4.0"},"reference-count":73,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2008,9,23]],"date-time":"2008-09-23T00:00:00Z","timestamp":1222128000000},"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":[[2009,1]]},"abstract":"<jats:sec><jats:label\/><jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Several cytochromes P450 (CYPs) have been implicated in the metabolism of methadone, but there is no consensus on their relative contributions to overall disposition and hence variability in response.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Variability in CYP3A4 activity has statistically significant but nonetheless modest influence on the oral clearance of methadone and its enantiomers.<\/jats:p><jats:p>\u2022\u2003However, CYPs 1A2 and 2D6 appear to have no impact at all.<\/jats:p><\/jats:sec><jats:sec><jats:title>AIMS<\/jats:title><jats:p>To investigate the influence of different cytochrome P450 (CYP) activities and other potential covariates on the disposition of methadone in patients on methadone maintenance therapy (MMT).<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Eighty\u2010eight patients (58 male; 21\u201355 years; 84 White) on MMT were studied. CYP2D6 activity [3\u2003h plasma metabolic ratio of dextromethorphan (DEX) to dextrorphan (DOR)] was determined in 44 patients (29 male; 24\u201355 years), CYP1A2 activity (salivary caffeine elimination half\u2010life) in 44 patients (21 male; 24\u201355 years) and CYP3A activity (oral clearance of midazolam) in 49 patients (33 male; 23\u201355 years). Data on all three CYPs were obtained from 32 subjects. Total plasma concentrations of (<jats:italic>RS<\/jats:italic>)\u2010methadone and total and unbound plasma concentrations of both enantiomers were measured by LC\/MS. Population pharmacokinetics and subsequent multiple regression analysis were used to calculate methadone oral clearance and to identify its covariates.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Between 61 and 68% of the overall variation in total plasma trough concentrations of (<jats:italic>RS<\/jats:italic>)\u2010, (<jats:italic>R<\/jats:italic>)\u2010 and (<jats:italic>S<\/jats:italic>)\u2010methadone was explained by methadone dose, duration of addiction before starting MMT, CYP3A activity and illicit morphine use. CYP3A activity explained 22, 16, 15 and 23% of the variation in unbound (<jats:italic>R<\/jats:italic>)\u2010, unbound (<jats:italic>S<\/jats:italic>)\u2010, total (<jats:italic>RS<\/jats:italic>)\u2010 and total (<jats:italic>S<\/jats:italic>)\u2010methadone clearances, respectively. Neither CYP2D6 nor CYP1A2 activity was related to methadone disposition.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>CYP3A activity has a modest influence on methadone disposition. Inhibitors and inducers of this enzyme should be monitored in patients taking methadone.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2125.2008.03312.x","type":"journal-article","created":{"date-parts":[[2008,9,23]],"date-time":"2008-09-23T12:41:54Z","timestamp":1222173714000},"page":"29-37","source":"Crossref","is-referenced-by-count":45,"title":["Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment"],"prefix":"10.1111","volume":"67","author":[{"given":"Mohammad\u2010Reza","family":"Shiran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin 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