{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:59:56Z","timestamp":1785373196402,"version":"3.55.0"},"reference-count":38,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K09955"],"award-info":[{"award-number":["24K09955"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25H00302"],"award-info":[{"award-number":["25H00302"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>\n                      Eltrombopag, a thrombopoietin receptor agonist for aplastic anaemia, can cause hepatotoxicity. It is metabolized by uridine diphosphate\u2010glucuronosyltransferase (UGT) 1A1 to form an acyl glucuronide metabolite; however, the relationships among serum concentrations of the acyl glucuronide metabolite,\n                      <jats:italic>UGT1A1<\/jats:italic>\n                      genotypes and hepatotoxicity remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      We examined the serum concentrations of eltrombopag and its acyl glucuronide metabolite,\n                      <jats:italic>UGT1A1<\/jats:italic>\n                      genotypes and occurrence of hepatotoxicity (abnormal liver function tests or drug\u2010induced liver injury [DILI]) in 104 samples from 42 patients with aplastic anaemia receiving eltrombopag.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The concentrations of eltrombopag and its acyl glucuronide metabolite were significantly higher in samples with abnormal liver function than in those with normal liver function (23.0\u2009\u00b1\u200918.5\n                      <jats:italic>vs<\/jats:italic>\n                      . 10.6\u2009\u00b1\u20099.3\u00a0\u03bcg\/mL and 6.9\u2009\u00b1\u20094.5\n                      <jats:italic>vs<\/jats:italic>\n                      . 2.1\u2009\u00b1\u20091.2\u00a0\u03bcg\/mL, respectively). Receiver operating characteristic (ROC) analysis demonstrated that the concentration of the acyl glucuronide metabolite provided superior predictive accuracy for hepatotoxicity, with a threshold of 4.0\u00a0\u03bcg\/mL, compared with eltrombopag (area under the ROC curve, 0.83\n                      <jats:italic>vs<\/jats:italic>\n                      . 0.68). All patients with DILI had higher concentrations of the acyl glucuronide metabolite than the cutoff value. The incidence of hepatotoxicity differed across\n                      <jats:italic>UGT1A1<\/jats:italic>\n                      genotype: 43% in extensive metabolizers (EMs), 11% in intermediate metabolizers (IMs) and none in poor metabolizers (PMs). The formation of the acyl glucuronide metabolite was 1.5\u2010fold greater in EMs than in IMs\/PMs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings suggest that eltrombopag\u2010induced hepatotoxicity is dependent on the concentration of eltrombopag acyl glucuronide and influenced by\n                      <jats:italic>UGT1A1<\/jats:italic>\n                      genotype, highlighting the potential utility of serum acyl glucuronide monitoring and\n                      <jats:italic>UGT1A1<\/jats:italic>\n                      genotyping for preventing and managing the hepatotoxicity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70585","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T03:46:23Z","timestamp":1777434383000},"page":"2853-2862","source":"Crossref","is-referenced-by-count":0,"title":["Concentration dependency of an acyl glucuronide metabolite in eltrombopag\u2010induced hepatotoxicity: Role of\n                    <i>UGT1A1<\/i>\n                    genotype"],"prefix":"10.1002","volume":"92","author":[{"given":"Shun","family":"Oda","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences University of Tsukuba  Tsukuba Ibaraki Japan"},{"name":"Department of Pharmacy University of Tsukuba Hospital  Tsukuba Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2497-0063","authenticated-orcid":false,"given":"Kosuke","family":"Doki","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences University of Tsukuba  Tsukuba Ibaraki Japan"},{"name":"Department of Pharmacy University of Tsukuba Hospital  Tsukuba Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoshi","family":"Obara","sequence":"additional","affiliation":[{"name":"Department of Hematology, Institute of Medicine University of Tsukuba  Tsukuba Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiharu","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Tsukuba Hospital  Tsukuba Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamiko","family":"Sakata\u2010Yanagimoto","sequence":"additional","affiliation":[{"name":"Department of Hematology, Institute of Medicine University of Tsukuba  Tsukuba Ibaraki Japan"},{"name":"Division of Advanced Hemato\u2010Oncology, Transborder Medical Research Center University of Tsukuba  Tsukuba Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Homma","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences University of Tsukuba  Tsukuba Ibaraki Japan"},{"name":"Department of Pharmacy University of Tsukuba Hospital  Tsukuba Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa073275"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200931"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102017\u201004\u2010748707"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021012130"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V118.21.2228.2228"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2015.3180"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2918"},{"key":"e_1_2_10_9_1","unstructured":"Promacta: prescribing information.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2025\/022291s041 207027s020lbl.pdf. Revised June 2025. Accessed December 8 2025."},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.111.040170"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000522"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228\u2010022\u201003367\u20102"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691\u2010200302000\u201000001"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2006.11.023"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.3388"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2024.110903"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22272"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.02.006"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.190"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2009.01.008"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.58"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010019\u20100105\u20100"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000001307"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2020.104774"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.2353\/jmoldx.2008.080036"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70233"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70234"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200023337171"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009\u20102797(00)00253\u20102"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1613878"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1066"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185\u2010019\u201002683\u20101"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.772873"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.02699"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2430"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.582625"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/ped4.12411"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.19735"},{"key":"e_1_2_10_39_1","unstructured":"CAMPTOSAR: prescribing information.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2022\/020571Orig1s053lbl.pdf. Revised January 2022. Accessed December 8 2025."}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70585","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bcp.70585","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70585","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:27:20Z","timestamp":1785371240000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/bcp.70585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,28]]},"references-count":38,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/bcp.70585"],"URL":"https:\/\/doi.org\/10.1002\/bcp.70585","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,28]]}}}