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Some CYP2B6 allelic variants affect methadone metabolism in vitro and disposition in vivo. We assessed methadone metabolism by CYP2B6 minor variants in vitro. We also assessed the influence of CYP2B6 variants, and P450 oxidoreductase (POR) and CYP2C19 variants, on methadone clearance in surgical patients in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>CYP2B6 and P450 oxidoreductase variants were coexpressed with cytochrome <jats:italic>b<\/jats:italic><jats:sub>5<\/jats:sub>. The metabolism of methadone racemate and enantiomers was measured at therapeutic concentrations and intrinsic clearances were determined. Adolescents receiving methadone for surgery were genotyped for <jats:italic>CYP2B6<\/jats:italic>, <jats:italic>CYP2C19<\/jats:italic> and <jats:italic>POR<\/jats:italic>, and methadone clearance and metabolite formation clearance were determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In vitro, CYP2B6.4 was more active than wild\u2010type CYP2B6.1. CYPs 2B6.5, 2B6.6, 2B6.7, 2B6.9, 2B6.17, 2B6.19 and 2B6.26 were less active. CYPs 2B6.16 and 2B6.18 were inactive. CYP2B6.1 expressed with POR variants POR.28, POR.5 and P228L had lower rates of methadone metabolism than wild\u2010type reductase. In vivo, methadone clinical clearance decreased linearly with the number of <jats:italic>CYP2B6<\/jats:italic> slow metabolizer alleles, but was not different in CYP2C19 slow or rapid metabolizer phenotypes, or in carriers of the <jats:italic>POR*28<\/jats:italic> allele.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Several CYP2B6 and POR variants were slow metabolizers of methadone in vitro. Polymorphisms in <jats:italic>CYP2B6<\/jats:italic>, but not <jats:italic>CYP2C19<\/jats:italic> or <jats:italic>P450 reductase<\/jats:italic>, affected methadone clearance in vivo. <jats:italic>CYP2B6<\/jats:italic> polymorphisms 516G&gt;T and 983T&gt;C code for canonical loss of function variants and should be assessed when considering genetic influences on clinical methadone disposition. These complementary translational in vitro and in vivo results inform on pharmacogenetic variability affecting methadone disposition in patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15393","type":"journal-article","created":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T05:10:07Z","timestamp":1652245807000},"page":"4881-4893","source":"Crossref","is-referenced-by-count":12,"title":["Methadone pharmacogenetics in vitro and in vivo: Metabolism by CYP2B6 polymorphic variants and genetic variability in paediatric disposition"],"prefix":"10.1111","volume":"88","author":[{"given":"Pan\u2010Fen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Duke University  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshuman","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Perioperative Care University of California  San Francisco CA 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