{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:56:47Z","timestamp":1792022207960,"version":"4.4.0"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,12,14]],"date-time":"2024-12-14T00:00:00Z","timestamp":1734134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>Atazanavir has been reported to increase total serum bilirubin level up to ninefold. It is widely believed that the observed total bilirubin elevation is primarily due to UGT1A1 inhibition. However, UGT enzymes are well\u2010known as a low\u2010affinity and high\u2010capacity system, and the observed drug\u2013drug interaction mediated by UGTs is usually less than twofold. There were discrepancies in the explanation of total bilirubin elevation due to UGT1A1 inhibition alone, suggesting the contribution of other mechanism(s) to the interaction. As atazanavir is a potent OATP1B1\/3 inhibitor and the hepatic uptake of both unconjugated and conjugated bilirubin are mediated by OATP1B1\/3, these transporters could be involved in the bilirubin\u2013atazanavir interaction. To better understand the roles of UGT1A1 and OATP1B1\/3 in this interaction, it would be useful to characterize the contribution of each individual pathway to the interaction. As multiple compounds, pathways, and potentially UGT1A1 polymorphism are involved, a thorough physiologically\u2010based pharmacokinetic (PBPK) analysis was utilized to integrate the information from various relevant <jats:italic>in vitro<\/jats:italic> and clinical studies to quantitatively estimate the contribution of UGT1A1 and OATP1B1\/3 inhibition to the interaction between bilirubin and atazanavir. The PBPK analysis indicated that UGT1A1 inhibition plays a modest role in bilirubin and atazanavir interaction contributing less than 33%. The results also suggested that unconjugated bilirubin is less sensitive than raltegravir upon UGT1A1 inhibition, therefore, unconjugated bilirubin may not be a useful endogenous biomarker for UGT1A1 inhibition. The analysis demonstrated that the metabolism of unconjugated bilirubin shares common features of other UGT enzyme\u2010mediated reactions.<\/jats:p>","DOI":"10.1002\/cpt.3529","type":"journal-article","created":{"date-parts":[[2024,12,14]],"date-time":"2024-12-14T12:28:16Z","timestamp":1734179296000},"page":"497-509","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Inhibition of <scp>OATP1B1<\/scp>\/3 Rather Than <scp>UGT1A1<\/scp> May Be the Major Cause of the Bilirubin Elevation After Atazanavir Administration"],"prefix":"10.1002","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3317-0386","authenticated-orcid":false,"given":"Jin","family":"Dong","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences BioPharmaceuticals R&amp;D, AstraZeneca  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3415-8917","authenticated-orcid":false,"given":"Pradeep","family":"Sharma","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences BioPharmaceuticals R&amp;D, AstraZeneca  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2648-3066","authenticated-orcid":false,"given":"Rasha","family":"Emara","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy University of the Pacific  Stockton California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2514-1970","authenticated-orcid":false,"given":"Derek","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy University of the Pacific  Stockton California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8261-8116","authenticated-orcid":false,"given":"Weifeng","family":"Tang","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences BioPharmaceuticals R&amp;D, AstraZeneca  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2673-1069","authenticated-orcid":false,"given":"Diansong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences BioPharmaceuticals R&amp;D, AstraZeneca  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0668-7304","authenticated-orcid":false,"given":"David W.","family":"Boulton","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences BioPharmaceuticals R&amp;D, AstraZeneca  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9643-1638","authenticated-orcid":false,"given":"Mats","family":"N\u00e5g\u00e5rd","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences BioPharmaceuticals R&amp;D, AstraZeneca  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2925-697X","authenticated-orcid":false,"given":"Miki S.","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy University of the Pacific  Stockton California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,14]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108459"},{"key":"e_1_2_9_2_1","unstructured":"European Medicines Agency.ICH M12 on drug interaction studies \u2010 Scientific guideline<https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/draft\u2010ich\u2010guideline\u2010m12\u2010drug\u2010interaction\u2010studies\u2010step\u20102b_en.pdf>."},{"key":"e_1_2_9_3_1","unstructured":"Certara.Certara drug interaction database (DIDB)<https:\/\/www.druginteractionsolutions.org\/>."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.619"},{"key":"e_1_2_9_5_1","first-page":"79","volume-title":"Surgery of the Liver, Biliary Tract and Pancreas","author":"Nakeeb A.","year":"2007"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.113.055772"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2015.247"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2011.03947.x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1086\/588794"},{"key":"e_1_2_9_10_1","unstructured":"Evaluation of the drug\u2010drug interaction potential between cobicistat\u2010boosted protease inhibitors and statins(2017) [abstract O_04].18th international workshop on clinical pharmacology of antiviral therapy."},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.269"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.110.211789"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.314"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200218666170724110818"},{"key":"e_1_2_9_15_1","unstructured":"European Medicines Agency.Nexavar (Sorafenib) product information<https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/nexavar\u2010epar\u2010product\u2010information_en.pdf>."},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2484"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12541"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.936"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.tpj.6500221"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0b013e318203e7e7"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.016310"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs-2018-0196"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e32832bcf7b"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.2147\/CEG.S64283"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1695"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-758-7_11"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2021.105951"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/hiv.12121"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e32834b4d48"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1176775"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3851\/IMP1673"},{"key":"e_1_2_9_32_1","first-page":"987","article-title":"Comparison of tolerability and impact on metabolic profiles of antiretroviral regimens containing Darunavir\/ritonavir or Darunavir\/Cobicistat in Romanian HIV infected patients","volume":"9","author":"Marin R.C.","year":"2021","journal-title":"Biomedicine"},{"key":"e_1_2_9_33_1","unstructured":"Cleveland Clinic.Bilirubin Test<https:\/\/my.clevelandclinic.org\/health\/diagnostics\/17845\u2010bilirubin> (2023)."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3529","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T08:52:10Z","timestamp":1752828730000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3529"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,14]]},"references-count":33,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/cpt.3529"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3529","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,14]]},"assertion":[{"value":"2024-10-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}