{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T02:35:49Z","timestamp":1789094149490,"version":"build-2803163510"},"reference-count":17,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T00:00:00Z","timestamp":1628985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The cytochrome P450 (CYP) 2D6 enzyme exhibits large interindividual differences in metabolic activity. Patients are commonly assigned a CYP2D6 phenotype based on their <jats:italic>CYP2D6<\/jats:italic>\u00a0genotype, but there is a lack of consensus on how to translate genotypes into phenotypes, causing inconsistency in genotype\u2010based dose recommendations. The aim of this study was to quantify and compare the impact of different <jats:italic>CYP2D6<\/jats:italic>\u00a0genotypes and alleles on CYP2D6\u00a0metabolism using a large clinical data set. A population pharmacokinetic (popPK) model of tedatioxetine and its CYP2D6\u2010dependent metabolite was developed based on pharmacokinetic data from 578\u00a0subjects. The CYP2D6\u2010mediated metabolism was quantified for each subject based on estimates from the final popPK model, and CYP2D6 activity scores were calculated for each allele using multiple linear regression. The activity scores estimated for the decreased function alleles were 0.46 (<jats:italic>CYP2D6*9<\/jats:italic>), 0.34 (<jats:italic>CYP2D6*10<\/jats:italic>), 0.01 (<jats:italic>CYP2D6*17<\/jats:italic>), 0.65 (<jats:italic>CYP2D6*29<\/jats:italic>), and 0.21 (<jats:italic>CYP2D6*41<\/jats:italic>). The <jats:italic>CYP2D6*17<\/jats:italic> and <jats:italic>CYP2D6*41<\/jats:italic> alleles were thus associated with the lowest CYP2D6 activity, although only the difference to the <jats:italic>CYP2D6*9<\/jats:italic> allele was shown to be statistically significant (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.02 and <jats:italic>p<\/jats:italic>\u00a0=\u00a00.05, respectively). The study provides new <jats:italic>in vivo<\/jats:italic> evidence of the enzyme function of different <jats:italic>CYP2D6<\/jats:italic>\u00a0genotypes and alleles. Our findings suggest that the activity score assigned to <jats:italic>CYP2D6*41<\/jats:italic>\u00a0should be revisited, whereas <jats:italic>CYP2D6*17<\/jats:italic> appears to exhibit substrate\u2010specific behavior. Further studies are needed to confirm the findings and to improve the understanding of <jats:italic>CYP2D6<\/jats:italic>\u00a0genotype\u2013phenotype relationships across substrates.<\/jats:p>","DOI":"10.1002\/psp4.12635","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T09:02:34Z","timestamp":1619859754000},"page":"983-993","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cytochrome P450 <i>2D6<\/i> genotype\u2013phenotype characterization through population pharmacokinetic modeling of tedatioxetine"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0266-4065","authenticated-orcid":false,"given":"Trine","family":"Frederiksen","sequence":"first","affiliation":[{"name":"PKPD Modelling &amp; Simulation, Experimental Medicine H. Lundbeck A\/S Valby Denmark"},{"name":"Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health University of Southern Denmark Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Areberg","sequence":"additional","affiliation":[{"name":"PKPD Modelling &amp; Simulation, Experimental Medicine H. Lundbeck A\/S Valby Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Schmidt","sequence":"additional","affiliation":[{"name":"PKPD Modelling &amp; Simulation, Experimental Medicine H. Lundbeck A\/S Valby Denmark"},{"name":"Clinical Pharmacology, Experimental Medicine H. Lundbeck A\/S Valby Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tore Bjerregaard","family":"Stage","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health University of Southern Denmark Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Br\u00f8sen","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health University of Southern Denmark Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.80"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12692"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200215666140202215316"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13788"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1007"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.107.015354"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2005.04.001"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1972"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.1996.00489.x"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.2165\/11318070-000000000-00000"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.tpj.6500378"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.fpc.0000230112.96086.e0"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14500"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14626"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2017.03.007"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2017.05.018"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1643"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12635","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.12635","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12635","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T04:57:10Z","timestamp":1721019430000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.12635"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,15]]},"references-count":17,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["10.1002\/psp4.12635"],"URL":"https:\/\/doi.org\/10.1002\/psp4.12635","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,15]]},"assertion":[{"value":"2020-11-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}