{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:58:01Z","timestamp":1790927881909,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,10]]},"abstract":"\n This study investigated genetic determinants of the pharmacokinetics of the CYP2C8 index drugs repaglinide and gemfibrozil, and their interaction in healthy participants. Sequencing data from a study with montelukast revealed a novel functional\n CYP2C8<\/jats:italic>\n allele (rs2071426,\n CYP2C8*19<\/jats:italic>\n ), predicted to create an intronic splice donor site. In human liver samples,\n CYP2C8*19<\/jats:italic>\n associated with transcript\u2010specific changes in\n CYP2C8<\/jats:italic>\n mRNA expression, reduced CYP2C8 protein expression, and decreased enzyme activity. Consistently, participants with the\n CYP2C8*19<\/jats:italic>\n \/\n *19<\/jats:italic>\n genotype had 45% greater area under the plasma repaglinide concentration\u2013time curve from time zero to infinity (AUC\n 0\u2010\u221e<\/jats:sub>\n ) than participants with\n CYP2C8*1<\/jats:italic>\n \/\n *1<\/jats:italic>\n (\n P<\/jats:italic>\n \u2009=\u20091.6\u2009\u00d7\u200910\n \u22124<\/jats:sup>\n ). Participants with\n CYP2C8*1<\/jats:italic>\n \/\n *3<\/jats:italic>\n had 26% smaller AUC\n 0\u2010\u221e<\/jats:sub>\n (\n P<\/jats:italic>\n \u2009=\u20090.0033) and those with\n CYP2C8*1<\/jats:italic>\n \/\n *4<\/jats:italic>\n had 51% greater AUC\n 0\u2010\u221e<\/jats:sub>\n (\n P<\/jats:italic>\n \u2009=\u20098.2\u2009\u00d7\u200910\n \u22124<\/jats:sup>\n ). The fold increase in repaglinide AUC\n 0\u2010\u221e<\/jats:sub>\n caused by gemfibrozil was 36% (\n P<\/jats:italic>\n \u2009=\u20091.3\u2009\u00d7\u200910\n \u22124<\/jats:sup>\n ) smaller in\n CYP2C8*19<\/jats:italic>\n \/\n *19<\/jats:italic>\n participants than in\n CYP2C8*1<\/jats:italic>\n \/\n *1<\/jats:italic>\n participants. In a genome\u2010wide association study (GWAS),\n SLCO1B1<\/jats:italic>\n c.521\u2009T>C (rs4149056) associated with increased repaglinide AUC\n 0\u2010\u221e<\/jats:sub>\n (\n P<\/jats:italic>\n \u2009=\u20094.5\u2009\u00d7\u200910\n \u221215<\/jats:sup>\n ;\n n<\/jats:italic>\n \u2009=\u2009172) and\n SLCO1A2<\/jats:italic>\n variants associated with decreased AUC\n 0\u2010\u221e<\/jats:sub>\n (\n P<\/jats:italic>\n \u2009<\u200910\n \u22128<\/jats:sup>\n ). In a GWAS of repaglinide after gemfibrozil pretreatment,\n SLCO1C1<\/jats:italic>\n variants associated with decreased AUC\n 0\u2010\u221e<\/jats:sub>\n (\n P<\/jats:italic>\n \u2009<\u20091.6\u2009\u00d7\u200910\n \u22128<\/jats:sup>\n ;\n n<\/jats:italic>\n \u2009=\u200966). Participants with the poor function\n SLCO1B1<\/jats:italic>\n genotype showed a 32% smaller fold increase in repaglinide AUC\n 0\u2010\u221e<\/jats:sub>\n following gemfibrozil than participants with the normal function\n SLCO1B1<\/jats:italic>\n genotype (\n P<\/jats:italic>\n \u2009=\u20090.0045). This study characterizes\n CYP2C8*19<\/jats:italic>\n as a novel decreased function allele and shows that\n CYP2C8<\/jats:italic>\n and\n SLCO1B1<\/jats:italic>\n genotypes affect the gemfibrozil\u2013repaglinide interaction.\n <\/jats:p>","DOI":"10.1002\/cpt.70376","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T03:53:08Z","timestamp":1782964388000},"page":"966-978","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of a Functional\n \n CYP2C8<\/i>\n <\/scp>\n Variant Allele that Alters Splicing, Reduces Protein Expression, and Increases Drug Exposure"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3348-1325","authenticated-orcid":false,"given":"Anssi J. 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