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Methadone is also used for acute and chronic pain. As use for chronic pain has grown, so too have adverse events. Constitutive and acquired (drug interactions) inter\u2010 and intraindividual variability in methadone pharmacokinetics and pharmacodynamics confounds reliable clinical use. Identification of enzymes and transporters responsible for methadone disposition has been a long\u2010sought ideal. Initial in vitro studies identified CYP3A4 as metabolizing methadone. Subsequently, by extrapolation, CYP3A4 was long assumed to be responsible for clinical methadone disposition. However, CYP2B6 is also a major catalyst of methadone metabolism in vitro. It has now been unequivocally established that CYP2B6, not CYP3A4, is the principal determinant of methadone metabolism, clearance, elimination, and plasma concentrations in humans. Methadone disposition is susceptible to inductive and inhibitory drug interactions. CYP2B6 genetics also influences methadone metabolism and clearance, which were diminished in <jats:italic>CYP2B6*6<\/jats:italic> carriers and increased in <jats:italic>CYP2B6*4<\/jats:italic> carriers. <jats:italic>CYP2B6<\/jats:italic> genetics can explain, in part, interindividual variability in methadone metabolism and clearance. Thus, both constitutive variability due to <jats:italic>CYP2B6<\/jats:italic> genetics, and CYP2B6\u2010mediated drug interactions, can alter methadone disposition, clinical effect, and drug safety. Methadone is not a substrate for major influx or efflux transporters.<\/jats:p>","DOI":"10.1002\/cpdd.326","type":"journal-article","created":{"date-parts":[[2017,3,6]],"date-time":"2017-03-06T15:25:23Z","timestamp":1488813923000},"page":"125-134","source":"Crossref","is-referenced-by-count":90,"title":["Current Concepts in Methadone Metabolism and Transport"],"prefix":"10.1002","volume":"6","author":[{"given":"Evan D.","family":"Kharasch","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Washington University in St. Louis  St. Louis MO USA"},{"name":"Department of Biochemistry and Biophysics Washington University in St. Louis  St. Louis MO USA"},{"name":"The Center for Clinical Pharmacology St. Louis College of Pharmacy and Washington University in St. Louis School of Medicine  St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,3,6]]},"reference":[{"key":"e_1_2_6_2_1","first-page":"493","article-title":"Vital signs: risk for overdose from methadone used for pain relief\u2014United States, 1999\u20102010","volume":"61","author":"Paulozzi LJ","year":"2012","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6450a3"},{"key":"e_1_2_6_4_1","unstructured":"Methadone mortality\u2014A reassessment. 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