{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T02:36:05Z","timestamp":1785551765729,"version":"3.56.0"},"reference-count":35,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T00:00:00Z","timestamp":1599523200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:p>Patients with autosomal dominant polycystic kidney disease (ADPKD) exhibit enhanced susceptibility to tolvaptan hepatotoxicity relative to other patient populations. In a rodent model of ADPKD, the expression and function of the biliary efflux transporter Mrp2 was reduced, and biliary excretion of a major tolvaptan metabolite (DM\u20104103) was decreased. The current study investigated whether reduced biliary efflux could contribute to increased susceptibility to tolvaptan\u2010associated hepatotoxicity using a quantitative systems toxicology (QST) model (DILIsym). QST simulations revealed that decreased biliary excretion of DM\u20104103, but not tolvaptan, resulted in substantial hepatic accumulation of bile acids, decreased electron transport chain activity, reduced hepatic adenosine triphosphate concentrations, and an increased incidence of hepatotoxicity. <jats:italic>In vitro<\/jats:italic> experiments (C\u2010DILI) with sandwich\u2010cultured human hepatocytes and HepaRG cells were performed to assess tolvaptan\u2010associated hepatotoxic effects when MRP2 was impaired by chemical inhibition (MK571, 50\u00a0\u00b5M) or genetic knockout, respectively. Tolvaptan (64\u00a0\u00b5M, 24\u2010hour) treatment of these cells increased cytotoxicity markers up to 27.9\u2010fold and 1.6\u2010fold, respectively, when MRP2 was impaired, indicating that MRP2 dysfunction may be involved in tolvaptan\u2010associated cytotoxicity. In conclusion, QST modeling supported the hypothesis that reduced biliary efflux of tolvaptan and\/or DM\u20104103 could account for increased susceptibility to tolvaptan\u2010associated hepatotoxicity; <jats:italic>in vitro<\/jats:italic> experiments implicated MRP2 dysfunction as a key factor in susceptibility. QST simulations revealed that DM\u20104103 may contribute to hepatotoxicity more than the parent compound. ADPKD progression and gradual reduction in MRP2 activity may explain why acute liver events can occur well after one\u00a0year of tolvaptan treatment.<\/jats:p>","DOI":"10.1002\/cpt.2007","type":"journal-article","created":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T04:55:17Z","timestamp":1596516917000},"page":"433-442","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Quantitative Systems Toxicology Modeling Predicts that Reduced Biliary Efflux Contributes to Tolvaptan Hepatotoxicity"],"prefix":"10.1111","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-8844","authenticated-orcid":false,"given":"James J.","family":"Beaudoin","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy University of North Carolina Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4372-3711","authenticated-orcid":false,"given":"William J.","family":"Brock","sequence":"additional","affiliation":[{"name":"Brock Scientific Consulting LLC Montgomery Village Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9541-8917","authenticated-orcid":false,"given":"Paul B.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy University of North Carolina Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1945-4929","authenticated-orcid":false,"given":"Kim L. 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