{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T05:08:12Z","timestamp":1773032892382,"version":"3.50.1"},"reference-count":45,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"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":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Bilirubin is a breakdown product of erythrocytes and plays a crucial role in elimination of heme\u2010containing proteins. After its synthesis in the reticuloendothelial system, unconjugated bilirubin is released into plasma and taken up into the liver. In hepatocytes, bilirubin is conjugated and excreted into the gastrointestinal tract via bile, where it is further converted to urobilinoids. There are various genetic factors causing abnormal bilirubin levels in plasma, such as Gilbert syndrome, Crigler\u2010Najjar syndrome, Dubin\u2010Johnson syndrome, and Rotor syndrome. To better understand bilirubin metabolism and its disorders, this study develops a physiologically based computational model incorporating published literature as well as real\u2010world clinical data from the Explorys database. The model simulates bilirubin levels in both healthy individuals and patients with disorders of bilirubin metabolism. Population simulations show that Gilbert syndrome requires a substantial reduction in UDP\u2010glucuronosyltransferase 1A1 activity, while Crigler\u2010Najjar syndrome requires near\u2010complete loss of its function. In contrast, Dubin\u2010Johnson syndrome is characterized by a significant impairment of multidrug resistance\u2010associated protein 2 activity. To also illustrate model behavior under targeted perturbations, we simulated administration of atazanavir in healthy individuals and patients with Gilbert syndrome to investigate its effect on bilirubin levels. Relative to baseline, unconjugated bilirubin maximum concentration (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) increased by 34% in healthy individuals but by 67% in Gilbert syndrome. Overall, this study provides a conceptual and mechanistically informed framework for studying bilirubin homeostasis and the functional consequences of drug administration in health and disease.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70183","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T14:50:06Z","timestamp":1768575006000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development of a Physiologically Based Model of Bilirubin Metabolism in Health and Disease and Its Comparison With Real\u2010World Data"],"prefix":"10.1002","volume":"15","author":[{"given":"Ahenk Zeynep","family":"Sayin","sequence":"first","affiliation":[{"name":"Institute for Systems Medicine With Focus on Organ Interaction University Hospital RWTH Aachen  Aachen Germany"},{"name":"Center for Computational Life Sciences, RWTH Aachen University  Aachen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8741-7786","authenticated-orcid":false,"given":"Lars","family":"Kuepfer","sequence":"additional","affiliation":[{"name":"Institute for Systems Medicine With Focus on Organ Interaction University Hospital RWTH Aachen  Aachen Germany"},{"name":"Center for Computational Life Sciences, RWTH Aachen University  Aachen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-1-4160-6189-2.00073-1"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.21037\/pm-21-15"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00405.2020"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-540-76839-5"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-49980-8_24"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.03.047"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11172647"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI106184"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-4809(75)90024-5"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.2147\/CEG.S438140"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.619"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3529"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12134"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.01192"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107922"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0209587"},{"key":"e_1_2_9_18_1","unstructured":"Merative \u201cMarketScan Explorys Database \u201dhttps:\/\/www.merative.com\/real\u2010world\u2010evidence\/real\u2010world\u2010data\u2010analytics."},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp4001348"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1478-5382(03)02342-4"},{"key":"e_1_2_9_21_1","unstructured":"A.Rohatgi \u201cWebPlotDigitizer \u201dVersion 4.7 https:\/\/automeris.io."},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(70)90017-3"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-007-9053-5"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1049\/enb.2017.0004"},{"key":"e_1_2_9_25_1","unstructured":"S. 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