{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:49:49Z","timestamp":1773190189228,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,12,14]],"date-time":"2024-12-14T00:00:00Z","timestamp":1734134400000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Venetoclax is a first\u2010in\u2010class orally administered B\u2010cell lymphoma\u20102 inhibitor used to treat chronic lymphocytic leukemia (CLL). Venetoclax is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 to its major metabolite M27, via M5, and M2, M3, and M4 via oxidation. Although venetoclax is a breakthrough in CLL treatment, managing drug safety and toxicity remains a clinical challenge. The objectives of this study were to investigate how individual CYP3A activity and protein expression affect hepatic venetoclax metabolism in\u00a0vitro and examine whether plasma 4\u03b2\u2010hydroxycholesterol (4\u03b2\u2010HC)\/cholesterol ratio can predict venetoclax metabolism in\u00a0vitro and in\u00a0vivo. In human liver microsomes (<jats:italic>n<\/jats:italic>\u2009=\u200920) and primary human hepatocytes (<jats:italic>n<\/jats:italic>\u2009=\u200915), venetoclax metabolite formation varied widely between donors and significantly correlated with CYP3A activity (midazolam 1\u2032\u2010hydroxylation) and CYP3A4 protein expression. Venetoclax metabolite formation positively correlated with 4\u03b2\u2010HC\/cholesterol ratio in plasma samples from the matched non\u2010infant donors (<jats:italic>n<\/jats:italic>\u2009=\u200914, ages 3\u201363\u2009years). In an observational pilot study of real\u2010world patients with CLL (<jats:italic>n<\/jats:italic>\u2009=\u200912, ages 56\u201384\u2009years) treated with venetoclax, the plasma M3\/venetoclax metabolic ratio negatively correlated with plasma 4\u03b2\u2010HC\/cholesterol ratio and positively correlated with patient age. Plasma 4\u03b2\u2010HC\/cholesterol ratio negatively correlated with patient age. Differences between the in\u00a0vitro data, which showed a positive association between venetoclax metabolism, hepatic CYP3A markers, and plasma 4\u03b2\u2010HC\/cholesterol ratio, and the in\u00a0vivo findings in patients with CLL could be due to age or other factors regulating plasma 4\u03b2\u2010HC\/cholesterol and\/or venetoclax disposition. Future studies with larger sample sizes are needed to investigate age\u2010related changes in venetoclax metabolism and plasma 4\u03b2\u2010HC\/cholesterol ratio.<\/jats:p>","DOI":"10.1111\/cts.70106","type":"journal-article","created":{"date-parts":[[2024,12,14]],"date-time":"2024-12-14T08:09:33Z","timestamp":1734163773000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Interindividual variability in <scp>CYP3A<\/scp>\u2010mediated venetoclax metabolism in\u00a0vitro and in\u00a0vivo in patients with chronic lymphocytic leukemia"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8731-1563","authenticated-orcid":false,"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 North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6228-2136","authenticated-orcid":false,"given":"Jessica L.","family":"Beers","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina at Chapel Hill Eshelman School of Pharmacy  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina at Chapel Hill Eshelman School of Pharmacy  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivian","family":"Truong","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina at Chapel Hill Eshelman School of Pharmacy  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5542-7799","authenticated-orcid":false,"given":"Zachary","family":"Brown","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina at Chapel Hill Eshelman School of Pharmacy  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2387-6676","authenticated-orcid":false,"given":"Benyam","family":"Muluneh","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina at Chapel Hill Eshelman School of Pharmacy  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0335-1079","authenticated-orcid":false,"given":"Catherine C.","family":"Coombs","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology University of North Carolina at Chapel Hill School of Medicine  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9388-9800","authenticated-orcid":false,"given":"Klarissa D.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina at Chapel Hill Eshelman School of Pharmacy  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,12,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1586\/era.11.132"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020712-163955"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2764"},{"issue":"3","key":"e_1_2_10_5_1","first-page":"456","article-title":"Bcl\u20102 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome","volume":"10","author":"Robertson LE","year":"1996","journal-title":"Leukemia"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.858"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-016-9927-9"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/1060028016685803"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3048"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.116.071613"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.730"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-017-0529-1"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2017.09.027"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15061680"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3761"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-788786"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.193615"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1513257"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M201712200"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12425"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2008.03309.x"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.9479-17"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2018.09.028"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.5414\/CPP47709"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-021-01026-w"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1472"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13448"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2008.08.010"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.119.088823"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.109.031328"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.109.056705"},{"key":"e_1_2_10_32_1","unstructured":"Services U. S. D. o. H. a. H.Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.2017."},{"key":"e_1_2_10_33_1","unstructured":"FDA.Granix prescribing information.2014."},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2012.12.007"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2010.03773.x"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13394"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199937060-00004"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(94)90543-6"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.20179"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2019.108078"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-014-0140-7"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.294"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13144"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.03.008"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.11.033"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo13070799"},{"issue":"2","key":"e_1_2_10_47_1","first-page":"1011","article-title":"Interindividual variation in expression of P\u2010glycoprotein in normal human liver and secondary hepatic neoplasms","volume":"275","author":"Schuetz EG","year":"1995","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.0c00574"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.741"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T15:36:11Z","timestamp":1735054571000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12]]},"references-count":48,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1111\/cts.70106"],"URL":"https:\/\/doi.org\/10.1111\/cts.70106","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12]]},"assertion":[{"value":"2024-04-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70106"}}