{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T07:51:31Z","timestamp":1789026691775,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,9,12]],"date-time":"2019-09-12T00:00:00Z","timestamp":1568246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32GM08425"],"award-info":[{"award-number":["T32GM08425"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["M01-RR00750"],"award-info":[{"award-number":["M01-RR00750"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:p>We verified a physiologically\u2010based pharmacokinetic (PBPK) model to predict cytochrome P450 3A4\/5\u2010mediated drug\u2010drug interactions (DDIs). A midazolam (MDZ)\u2013ketoconazole (KTZ) interaction study in 24 subjects selected by <jats:italic>CYP3A5<\/jats:italic> genotype, and liquid chromatography and mass spectroscopy quantification of CYP3A4\/5 abundance from independently acquired and genotyped human liver (<jats:italic>n<\/jats:italic>\u00a0=\u00a0136) and small intestinal (<jats:italic>N<\/jats:italic>\u00a0=\u00a012) samples, were conducted. The observed <jats:italic>CYP3A5<\/jats:italic> genetic effect on MDZ systemic and oral clearance was successfully replicated by a mechanistic framework incorporating the proteomics\u2010informed CYP3A abundance and optimized small intestinal CYP3A4 abundance based on MDZ intestinal availability (F<jats:sub>G<\/jats:sub>) of 0.44. Furthermore, combined with a modified KTZ PBPK model, this framework recapitulated the observed geometric mean ratio of MDZ area under the curve (AUCR) following 200 or 400\u00a0mg KTZ, which was, respectively, 2.7\u20133.4 and 3.9\u20134.7\u2010fold in intravenous administration and 11.4\u201313.4 and 17.0\u201319.7\u2010fold in oral administration, with AUCR numerically lower (<jats:italic>P<\/jats:italic>\u00a0&gt;\u00a00.05) in CYP3A5 expressers than nonexpressers. In conclusion, the developed mechanistic framework supports dynamic prediction of CYP3A\u2010mediated DDIs in study planning by bridging DDIs between CYP3A5 expressers and nonexpressers.<\/jats:p>","DOI":"10.1002\/cpt.1596","type":"journal-article","created":{"date-parts":[[2019,7,29]],"date-time":"2019-07-29T16:08:44Z","timestamp":1564416524000},"page":"246-256","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Quantitative Prediction of CYP3A4\u2010 and CYP3A5\u2010Mediated Drug Interactions"],"prefix":"10.1111","volume":"107","author":[{"given":"Yingying","family":"Guo","sequence":"first","affiliation":[{"name":"Drug Disposition Eli Lilly and Company Lilly Corporate Center DC0714 Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aroonrut","family":"Lucksiri","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Care Faculty of Pharmacy Chiang Mai University Chiang Mai Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma L.","family":"Dickinson","sequence":"additional","affiliation":[{"name":"Drug Disposition Eli Lilly and Company Lilly Corporate Center DC0714 Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj K.","family":"Vuppalanchi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Indiana University School of Medicine Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna K.","family":"Hilligoss","sequence":"additional","affiliation":[{"name":"Department of Medicine Indiana University Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Hall","sequence":"additional","affiliation":[{"name":"Drug Disposition Eli Lilly and Company Lilly Corporate Center DC0714 Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,12]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.104.000794"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.105.008672"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2016.1163337"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2014.129"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apha.2018.04.007"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/86882"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0000000000000047"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920008783331121"},{"key":"e_1_2_10_9_1","first-page":"180","article-title":"Inhibition of cytochrome P\u2010450 3A (CYP3A) in human intestinal and liver microsomes: comparison of Ki values and impact of CYP3A5 expression","volume":"27","author":"Gibbs M.A.","year":"1999","journal-title":"Drug Metab. 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