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While <jats:italic>CYP2D6*2<\/jats:italic> and <jats:italic>CYP2D6*35<\/jats:italic> are presently designated as alleles encoding normal metabolism, this classification is based on moderate level evidence. Additionally, the role of the formerly called \u201cenhancer\u201d single nucleotide polymorphism (SNP) rs5758550 is unclear. In this study, the impacts of <jats:italic>CYP2D6*2, CYP2D6*35<\/jats:italic> and rs5758550 on CYP2D6 activity were investigated using risperidone clearance as CYP2D6 activity marker.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A joint parent-metabolite population pharmacokinetic model was used to describe 1,565 serum concentration measurements of risperidone and 9-hydroxyrisperidone in 512 subjects. Risperidone population clearance was modeled as the sum of a CYP2D6-independent clearance term and the partial clearances contributed from each individually expressed <jats:italic>CYP2D6<\/jats:italic> allele or haplotype. In addition to the well-characterized <jats:italic>CYP2D6<\/jats:italic> alleles (<jats:italic>*3-*6<\/jats:italic>, <jats:italic>*9<\/jats:italic>, <jats:italic>*10<\/jats:italic> and <jats:italic>*41<\/jats:italic>), <jats:italic>*2<\/jats:italic>, <jats:italic>*35<\/jats:italic> and two haplotypes assigned as <jats:italic>CYP2D6*2-rs5758550G<\/jats:italic> and <jats:italic>CYP2D6*2-rs5758550A<\/jats:italic> were evaluated.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Each evaluated <jats:italic>CYP2D6<\/jats:italic> allele was associated with significantly lower risperidone clearance than the reference normal function allele <jats:italic>CYP2D6*1<\/jats:italic> (p\u2009&lt;\u20090.001). Further, rs5758550 differentiated the effect of <jats:italic>CYP2D6*2<\/jats:italic> (p\u2009=\u20090.005). The haplotype-specific clearances for <jats:italic>CYP2D6*2-rs5758550A<\/jats:italic>, <jats:italic>CYP2D6*2-rs5758550G<\/jats:italic> and <jats:italic>CYP2D6*35<\/jats:italic> were estimated to 30%, 66% and 57%, respectively, relative to the clearance for <jats:italic>CYP2D6*1<\/jats:italic>. Notably, rs5758550 is in high linkage disequilibrium (R<jats:sup>2<\/jats:sup>\u2009&gt;\u20090.85) with at least 24 other SNPs and cannot be assigned as a functional SNP.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p><jats:italic>CYP2D6*2<\/jats:italic> and <jats:italic>CYP2D6*35<\/jats:italic> encode reduced risperidone clearance, and the extent of reduction for <jats:italic>CYP2D6*2<\/jats:italic> is differentiated by rs5758550<jats:italic>.<\/jats:italic> Genotyping of these haplotypes might improve the precision of genotype-guided prediction of CYP2D6-mediated clearance.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00228-024-03721-6","type":"journal-article","created":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T12:01:40Z","timestamp":1720094500000},"page":"1531-1541","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Impact of CYP2D6*2, CYP2D6*35, rs5758550, and related haplotypes on risperidone clearance in vivo"],"prefix":"10.1007","volume":"80","author":[{"given":"Elisabet","family":"St\u00f8rset","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Line Skute","family":"Br\u00e5ten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Ingelman-Sundberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inger","family":"Johansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Espen","family":"Molden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne Kristiansen","family":"Kringen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,4]]},"reference":[{"issue":"11","key":"3721_CR1","doi-asserted-by":"publisher","first-page":"689","DOI":"10.2165\/11318030-000000000-00000","volume":"48","author":"SF Zhou","year":"2009","unstructured":"Zhou SF (2009) Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. 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