{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:42:25Z","timestamp":1792208545625,"version":"4.4.0"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"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":[[2026,11]]},"abstract":"<jats:p>Rifampicin is a prototypical clinical inducer used in drug\u2013drug interaction (DDI) studies. However, the clinical relevance and predictability of rifampicin\u2010mediated hepatic transporter induction remain poorly defined. Conventional hepatocyte culture models fail to capture clinically relevant regulation of transporters and drug\u2010metabolizing enzymes (DMEs), particularly at the protein level. In this study, we characterized a liver tissue chip (LTC) as a new approach methodology (NAM) for long\u2010term transporter\u2010 and DME\u2010mediated induction risk assessment. Transporter\u2010certified\u00ae cryopreserved primary human hepatocytes from three donors were cultured in the LTC under recirculating flow with or without 10\u2009\u03bcM rifampicin for 7\u2009days. The LTC facilitated simultaneous mRNA\u2010protein quantification for transporters and mRNA\u2010protein\u2010activity profiling for cytochrome P450s (CYPs) within individual chips across treatment and control conditions. In addition, extracellular bile acid profiling and intracellular rifampicin concentrations were measured by LC\u2013MS\/MS. Rifampicin induced multiple transporters and enzymes at the protein level, including organic anion transporting polypeptide (OATP)2B1, P\u2010glycoprotein, CYP3A4, CYP2C19, and uridine 5\u2019\u2010diphospho\u2010glucuronosyltransferase (UGT)1A4. Induction patterns differed between transporter mRNA and protein in many cases, suggesting regulatory mechanisms beyond PXR\u2010mediated activation. Matched mRNA\u2010protein\u2010activity measurements of five CYP enzymes also revealed discrepancies in rifampicin\u2010mediated induction magnitude. Rifampicin altered bile acid composition, increasing taurine\u2010conjugated bile acids and inducing bile acid\u2010related genes. Measured intracellular rifampicin concentrations differed substantially from experimentally employed media concentrations. Overall, these findings demonstrate that the LTC enables integrated assessment of mRNA, protein, and activity measurements in addition to bile acid profiles and intracellular drug exposure, which may improve mechanistic understanding of induction processes.<\/jats:p>","DOI":"10.1002\/cpt.70418","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T06:21:23Z","timestamp":1786688483000},"page":"1368-1378","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated assessment of rifampicin\u2010mediated induction of transporters and drug\u2010metabolizing enzymes in a long\u2010term human liver tissue chip system"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5082-0168","authenticated-orcid":false,"given":"Mattie E.","family":"Hartauer","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6212-8291","authenticated-orcid":false,"given":"Raeanne M.","family":"Lanphier","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0504-5336","authenticated-orcid":false,"given":"Shivam","family":"Ohri","sequence":"additional","affiliation":[{"name":"Javelin Biotech Inc  Billerica Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4646-1249","authenticated-orcid":false,"given":"Jessica","family":"Snyder","sequence":"additional","affiliation":[{"name":"Javelin Biotech Inc  Billerica Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9977-1184","authenticated-orcid":false,"given":"Jacqueline B.","family":"Tiley","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1848-0121","authenticated-orcid":false,"given":"John K.","family":"Fallon","sequence":"additional","affiliation":[{"name":"Division of Pharmacoengineering and Molecular Pharmaceutics, and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1138-9149","authenticated-orcid":false,"given":"Henry","family":"Ho","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6922-223X","authenticated-orcid":false,"given":"Murat","family":"Cirit","sequence":"additional","affiliation":[{"name":"Javelin Biotech Inc  Billerica Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9927-0261","authenticated-orcid":false,"given":"Shiny Amala Priya","family":"Rajan","sequence":"additional","affiliation":[{"name":"Javelin Biotech Inc  Billerica Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1945-4929","authenticated-orcid":false,"given":"Kim L. 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