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Despite lacking <jats:italic>in vivo<\/jats:italic> evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of <jats:italic>CYP2D6*9<\/jats:italic>, <jats:italic>CYP2D6*10<\/jats:italic> and <jats:italic>CYP2D6*41<\/jats:italic> on CYP2D6 metabolism in a large patient population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 1003 patients (mainly Caucasians) with data on <jats:italic>CYP2D6<\/jats:italic> genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The <jats:italic>O<\/jats:italic>\u2010desmethyl\u2010to\u2010<jats:italic>N<\/jats:italic>\u2010desmethyl\u2010venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann\u2013Whitney) between carriers of <jats:italic>CYP2D6*9\u201310<\/jats:italic> (merged) and <jats:italic>CYP2D6*41<\/jats:italic>, either combined with <jats:italic>CYP2D6*1<\/jats:italic> or non\u2010coding (<jats:italic>null<\/jats:italic>) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of <jats:italic>CYP2D6*9\u201310<\/jats:italic> and <jats:italic>CYP2D6*41<\/jats:italic> activity scores.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>MR was significantly lower in carriers of <jats:italic>CYP2D6*41<\/jats:italic> than <jats:italic>CYP2D6*9\u201310<\/jats:italic> (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.002). The majority of <jats:italic>CYP2D6*41<\/jats:italic>\/<jats:italic>null<\/jats:italic> carriers (86.7%) had MR in the observed range of <jats:italic>CYP2D6null\/null<\/jats:italic> carriers compared with the minority of <jats:italic>CYP2D6*9\u201310<\/jats:italic>\/<jats:italic>null<\/jats:italic> carriers (17.4%). <jats:italic>CYP2D6<\/jats:italic> genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45\u201312.20), 3.55 (2.06\u20136.10), 1.33 (0.87\u20132.05) and 0.47 (0.35\u20130.61) in carriers of <jats:italic>CYP2D6*1\/null<\/jats:italic> (<jats:italic>n<\/jats:italic>\u00a0=\u00a0269), <jats:italic>CYP2D6*9\u201310\/null<\/jats:italic> (<jats:italic>n<\/jats:italic>\u00a0=\u00a017), <jats:italic>CYP2D6*41<\/jats:italic>\/<jats:italic>null<\/jats:italic> (<jats:italic>n<\/jats:italic>\u00a0=\u00a030) and <jats:italic>CYP2D6null\/null<\/jats:italic> (<jats:italic>n<\/jats:italic>\u00a0=\u00a095), respectively. Based on these estimates, the calculated activity score of <jats:italic>CYP2D6*41<\/jats:italic> was 0.095 compared to 0.34 for <jats:italic>CYP2D6*9\u201310<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>CYP2D6 metabolism measured as the <jats:italic>O\/N<\/jats:italic>\u2010desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of <jats:italic>CYP2D6*41 vs. CYP2D6*9\u201310<\/jats:italic>. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13788","type":"journal-article","created":{"date-parts":[[2018,10,12]],"date-time":"2018-10-12T17:50:03Z","timestamp":1539366603000},"page":"194-201","source":"Crossref","is-referenced-by-count":33,"title":["Significantly lower CYP2D6 metabolism measured as the <i>O\/N<\/i>\u2010desmethylvenlafaxine metabolic ratio in carriers of <i>CYP2D6*41<\/i> versus <i>CYP2D6*9<\/i> or <i>CYP2D6*10<\/i>: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients"],"prefix":"10.1111","volume":"85","author":[{"given":"Tore","family":"Haslemo","sequence":"first","affiliation":[{"name":"Center for Psychopharmacology Diakonhjemmet Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Eliasson","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institute Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marin M.","family":"Juki\u0107","sequence":"additional","affiliation":[{"name":"Section of Pharmacogenetics, Department of Physiology and Pharmacology Karolinska Institute  Stockholm Sweden"},{"name":"Department of Physiology, Faculty of Pharmacy University of Belgrade  Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Ingelman\u2010Sundberg","sequence":"additional","affiliation":[{"name":"Section of Pharmacogenetics, Department of Physiology and Pharmacology Karolinska Institute  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6190-2751","authenticated-orcid":false,"given":"Espen","family":"Molden","sequence":"additional","affiliation":[{"name":"Center for Psychopharmacology Diakonhjemmet Hospital  Oslo Norway"},{"name":"Department of Pharmaceutical Biosciences, School of Pharmacy University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,11,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082562"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.910"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2165\/11318070-000000000-00000"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2165\/11318030-000000000-00000"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.80"},{"key":"e_1_2_9_7_1","unstructured":"PharmGKB.Very Important Pharmacogene: CYP2D6 [online]. 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