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Ibrutinib is metabolized primarily via oxidation by cytochrome P450 (CYP) 3A4\/5 to M37 (the primary active metabolite), M34, and M25. The objectives of this study were to assess the relationship between formation of the major CYP3A\u2010specific ibrutinib metabolites in vitro and hepatic CYP3A activity and protein abundance, and to evaluate the utility of the endogenous CYP3A biomarker, plasma 4\u03b2\u2010hydroxycholesterol (4\u03b2\u2010HC) to cholesterol ratio, to predict ibrutinib metabolite formation in individual cadaveric donors with matching hepatocytes. Ibrutinib (5\u00a0\u03bcM) was incubated with single\u2010donor human liver microsomes (<jats:italic>n<\/jats:italic>\u00a0=\u00a020) and primary human hepatocytes (<jats:italic>n<\/jats:italic>\u00a0=\u00a015), and metabolites (M37, M34, and M25) were measured by liquid chromatography\u2010tandem mass spectrometry analysis. CYP3A4\/5 protein concentrations were measured by quantitative targeted absolute proteomics, and CYP3A activity was measured by midazolam 1\u2032\u2010hydroxylation. Ibrutinib metabolite formation positively correlated with midazolam 1\u2032\u2010hydroxylation in human liver microsomes and hepatocytes. Plasma 4\u03b2\u2010HC and cholesterol concentrations were measured in plasma samples obtained at the time of liver harvest from the same 15 donors with matching hepatocytes. Midazolam 1\u2032\u2010hydroxylation in hepatocytes correlated with plasma 4\u03b2\u2010HC\/cholesterol ratio. When an infant donor (1 year old) was excluded based on previous ontogeny studies, M37 and M25 formation correlated with plasma 4\u03b2\u2010HC\/cholesterol ratio in the remaining 14 donors (Spearman correlation coefficients [<jats:italic>r<\/jats:italic>] 0.62 and 0.67, respectively). Collectively, these data indicate a positive association among formation of CYP3A\u2010specific ibrutinib metabolites in human hepatocytes, hepatic CYP3A activity, and plasma 4\u03b2\u2010HC\/cholesterol ratio in the same non\u2010infant donors.<\/jats:p>","DOI":"10.1111\/cts.13448","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T15:59:25Z","timestamp":1668009565000},"page":"279-291","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Formation of <scp>CYP3A<\/scp>\u2010specific metabolites of ibrutinib in vitro is correlated with hepatic <scp>CYP3A<\/scp> activity and 4\u03b2\u2010hydroxycholesterol\/cholesterol ratio"],"prefix":"10.1111","volume":"16","author":[{"given":"Jonghwa","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina at Chapel Hill Eshelman School of Pharmacy  Chapel Hill 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