{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T22:45:56Z","timestamp":1768257956277,"version":"3.49.0"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,1,7]],"date-time":"2013-01-07T00:00:00Z","timestamp":1357516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2013,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Methadone <jats:italic>N<\/jats:italic>\u2010demethylation <jats:italic>in vitro<\/jats:italic> is catalyzed by hepatic cytochrome P4502B6 (CYP2B6) and CYP3A4, but clinical disposition is often attributed to CYP3A4. This investigation tested the hypothesis that CYP2B6 is a prominent CYP isoform responsible for clinical methadone <jats:italic>N<\/jats:italic>\u2010demethylation and clearance, using the <jats:italic>in vivo<\/jats:italic> mechanism\u2010based CYP2B6 inhibitor ticlopidine, given orally for 4 days. A preliminary clinical investigation with the CYP3A4\/5 substrate probe alfentanil established that ticlopidine did not inhibit intestinal or hepatic CYP3A4\/5. Subjects received intravenous plus oral (deuterium\u2010labeled) racemic methadone before and after ticlopidine. Ticlopidine significantly and stereoselectively (S\u2009&gt;\u2009R) inhibited methadone <jats:italic>N<\/jats:italic>\u2010demethylation, decreasing plasma metabolite\/methadone area under the curve ratios and metabolite formation clearances. Ticlopidine also significantly increased the dose\u2010adjusted plasma area under the curve for R\u2010 and S\u2010methadone by 20% and 60%, respectively, after both intravenous and oral dosing. CYP2B6 inhibition reduces methadone <jats:italic>N<\/jats:italic>\u2010demethylation and clearance, and alters methadone concentrations, demonstrating an important role for CYP2B6 in clinical methadone disposition.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcph.1","type":"journal-article","created":{"date-parts":[[2013,2,27]],"date-time":"2013-02-27T06:23:47Z","timestamp":1361946227000},"page":"305-313","source":"Crossref","is-referenced-by-count":70,"title":["Role of Cytochrome P4502B6 in Methadone Metabolism and Clearance"],"prefix":"10.1002","volume":"53","author":[{"given":"Evan D.","family":"Kharasch","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Division of Clinical and Translational Research Washington University in St. Louis St. Louis, MO USA"},{"name":"Department of Biochemistry and Molecular Biophysics Washington University in St. Louis St. Louis, MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristi","family":"Stubbert","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Division of Clinical and Translational Research Washington University in St. Louis St. Louis, MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,1,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-010-0793-6"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0b013e3181fec9a3"},{"key":"e_1_2_7_4_1","first-page":"CD003971","article-title":"Methadone for cancer pain","author":"Nicholson AB.","year":"2007","journal-title":"Cochrane Database Syst Rev."},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2008.10.008"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200241140-00003"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2004.05.003"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.110.032474"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx950116m"},{"key":"e_1_2_7_10_1","first-page":"1347","article-title":"The involvement of cytochrome P450 3A4 in the N\u2010demethylation of L\u2010a\u2010acetylmethadol (LAAM), norLAAM, and methadone","volume":"25","author":"Moody DE","year":"1997","journal-title":"Drug Metab Dispos."},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2008.03312.x"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1521-0391.2009.00005.x"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.3109\/00952990.2010.540279"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.aids.0000183628.20041.f2"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.104"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2008.12.009"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181986a9a"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3182423478"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/chir.10303"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.117580"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181642938"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-7843.2010.00628.x"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01600-07"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.09.012"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0b013e318222b5dd"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.276"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.056127"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2005.02.010"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1570-0232(04)00541-0"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100237"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi010254c"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270005280077"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.2000.00272.x"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.140"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270010388651"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.1999.00921.x"},{"key":"e_1_2_7_37_1","first-page":"1123","article-title":"Evaluation of the contribution of cytochrome P450 3A4 to human liver microsomal bupropion hydroxylation","volume":"29","author":"Faucette SR","year":"2001","journal-title":"Drug Metab Dispos."},{"key":"e_1_2_7_38_1","article-title":"CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction","author":"Levran O","year":"2012","journal-title":"Addict Biol"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019527"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2005.09.010"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2006.10.004"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt1975182180"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00644967"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcph.1","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T03:00:45Z","timestamp":1698634845000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1,7]]},"references-count":42,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2013,3]]}},"alternative-id":["10.1002\/jcph.1"],"URL":"https:\/\/doi.org\/10.1002\/jcph.1","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,1,7]]}}}