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Fifty\u2010three head and neck cancer patients receiving oral tramadol were enrolled. The plasma concentrations of tramadol, <jats:italic>O<\/jats:italic>\u2010desmethyltramadol (ODT) and <jats:italic>N<\/jats:italic>\u2010desmethyltramadol (NDT) enantiomers were determined. The CYP2D6 activity score (AS) and degree of cachexia progression were assessed according to genotype and the Glasgow Prognostic Score (GPS), respectively. The enantiomeric ratio of NDT was (+)\u2010form dominant in all patients. CYP2D6 AS had negative correlations with the plasma concentrations of (+)\u2010NDT and (\u2212)\u2010NDT. The plasma concentrations of (+)\u2010tramadol and (+)\u2010ODT were higher in patients with GPS 1 or 2 than in those with GPS 0. Lower metabolic ratios to NDT enantiomers were observed in patients with GPS 1 or 2. In patients with GPS 1 or 2, the plasma (\u2212)\u2010tramadol was associated with the incidence of central nervous system symptoms. In conclusion, CYP2D6 AS partially explained the contribution of CYP2D6 activity to plasma tramadol and its demethylated metabolite enantiomers. Additionally, cachexia progression elevated the plasma (+)\u2010tramadol and (+)\u2010ODT levels through the reduction of <jats:italic>N<\/jats:italic>\u2010demethylation of (+)\u2010tramadol.<\/jats:p>","DOI":"10.1111\/bcpt.13528","type":"journal-article","created":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T06:39:40Z","timestamp":1604212780000},"page":"472-481","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Impact of CYP2D6 activity and cachexia progression on enantiomeric alteration of plasma tramadol and its demethylated metabolites and their relationships with central nervous system symptoms in head and neck cancer patients"],"prefix":"10.1111","volume":"128","author":[{"given":"Koji","family":"Suzuki","sequence":"first","affiliation":[{"name":"Department of Hospital Pharmacy Hamamatsu University School of Medicine Hamamatsu Japan"},{"name":"Department of Clinical Pharmacology &amp; Genetics, School of Pharmaceutical Sciences University of Shizuoka Shizuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7447-3789","authenticated-orcid":false,"given":"Takafumi","family":"Naito","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Hamamatsu University School of Medicine Hamamatsu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hironari","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Hamamatsu University School of Medicine Hamamatsu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaito","family":"Shibata","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Hamamatsu University School of Medicine Hamamatsu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhide","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology Hamamatsu University School of Medicine Hamamatsu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunihiko","family":"Itoh","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology &amp; Genetics, School of Pharmaceutical Sciences University of Shizuoka Shizuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junichi","family":"Kawakami","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Hamamatsu University School of Medicine Hamamatsu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,11,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200443130-00004"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1734-1140(09)70159-8"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2015.11.010"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.105"},{"issue":"8","key":"e_1_2_8_6_1","first-page":"1146","article-title":"Identification of cytochrome P\u2010450 isoforms responsible for cis\u2010tramadol metabolism in human liver microsomes","volume":"29","author":"Subrahmanyam V","year":"2001","journal-title":"Drug Metab Dispos."},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002100000266"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40780-016-0059-2"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-018-2527-0"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000707"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1275"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.2133\/dmpk.DMPK-11-RG-078"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/jpm8020015"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100406"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-016-2116-z"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000634"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13059"},{"key":"e_1_2_8_18_1","unstructured":"FlockhartDA.Drug Interactions: Cytochrome P450 Drug Interaction Table. 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