{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:08:46Z","timestamp":1790179726452,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:p>Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can assess hepatic extraction, clearance, biliary excretion, and drug\u2013drug interaction (DDI). Eleven livers were included in the study, seven with a cirrhotic and four with a noncirrhotic disease background. After explantation of the diseased liver, NMP was initiated. After 120\u2009minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin, and furosemide; OATP1B1\/1B3, P\u2010gp, BCRP, and OCT1 model compounds) was administered to the portal vein and 120\u2009minutes later, a second bolus of the drug cocktail was co\u2010administered with perpetrator drugs to study relevant DDIs. The explanted livers showed good viability and functionality during 360\u2009minutes of NMP. Hepatic extraction ratios close to <jats:italic>in vivo<\/jats:italic> reported values were measured. Hepatic clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in maximum plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) of 11.50 and 2.89 times, respectively, compared with noncirrhotic livers. No major differences were observed for metformin and furosemide. Interaction of rosuvastatin or digoxin with perpetrator drugs were more pronounced in noncirrhotic livers compared with cirrhotic livers. Our results demonstrated that NMP of human diseased explanted livers is an excellent model to assess hepatic extraction, clearance, biliary excretion, and DDI. Gaining insight into pharmacokinetic profiles of OATP1B1\/1B3, P\u2010gp, BCRP, and OCT1 model compounds is a first step toward studying transporter functions in diseased livers.<\/jats:p>","DOI":"10.1002\/cpt.2905","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T08:50:04Z","timestamp":1681289404000},"page":"137-147","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Novel Explanted Human Liver Model to Assess Hepatic Extraction, Biliary Excretion and Transporter Function"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6114-3561","authenticated-orcid":false,"given":"Lianne J.","family":"Stevens","sequence":"first","affiliation":[{"name":"Department of Surgery Leiden University Medical Center (LUMC)  Leiden The Netherlands"},{"name":"LUMC Transplant Center Leiden University Medical Center (LUMC)  Leiden The Netherlands"},{"name":"The Netherlands Organization for Applied Scientific Research (TNO)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"Dubbeld","sequence":"additional","affiliation":[{"name":"Department of Surgery Leiden University Medical Center (LUMC)  Leiden The Netherlands"},{"name":"LUMC Transplant Center Leiden University Medical Center (LUMC)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason B.","family":"Doppenberg","sequence":"additional","affiliation":[{"name":"LUMC Transplant Center Leiden University Medical Center (LUMC)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6527-764X","authenticated-orcid":false,"given":"Bart","family":"van Hoek","sequence":"additional","affiliation":[{"name":"LUMC Transplant Center Leiden University Medical Center (LUMC)  Leiden The Netherlands"},{"name":"Department of Gastroenterology and Hepatology Leiden University Medical Center (LUMC)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aswin L.","family":"Menke","sequence":"additional","affiliation":[{"name":"The Netherlands Organization for Applied Scientific Research (TNO)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne M.","family":"Donkers","sequence":"additional","affiliation":[{"name":"The Netherlands Organization for Applied Scientific Research (TNO)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulnaser","family":"Alsharaa","sequence":"additional","affiliation":[{"name":"The Netherlands Organization for Applied Scientific Research (TNO)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan","family":"de Vries","sequence":"additional","affiliation":[{"name":"The Netherlands Organization for Applied Scientific Research (TNO)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter H.J.","family":"Vaes","sequence":"additional","affiliation":[{"name":"The Netherlands Organization for Applied Scientific Research (TNO)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9893-4415","authenticated-orcid":false,"given":"Catherijne A.J.","family":"Knibbe","sequence":"additional","affiliation":[{"name":"Division of Systems Biomedicine and Pharmacology Leiden Academic Center for Drug Research (LACDR) Leiden University, Leiden &amp; 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