{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T18:51:38Z","timestamp":1791485498625,"version":"4.3.4"},"reference-count":35,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,12,12]],"date-time":"2016-12-12T00:00:00Z","timestamp":1481500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["94507606"],"award-info":[{"award-number":["94507606"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aliment Pharmacol Ther"],"published-print":{"date-parts":[[2017,2]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in <jats:styled-content style=\"fixed-case\">IBD<\/jats:styled-content> patients, often related to high steady\u2010state 6\u2010methylmercaptopurine ribonucleotide (6\u2010<jats:styled-content style=\"fixed-case\">MMPR<\/jats:styled-content>) metabolite concentrations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To determine the predictive value of 6\u2010<jats:styled-content style=\"fixed-case\">MMPR<\/jats:styled-content> concentrations 1 week after treatment initiation (<jats:italic>T1<\/jats:italic>) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The cohort study consisted of the first 270 <jats:styled-content style=\"fixed-case\">IBD<\/jats:styled-content> patients starting thiopurine treatment as part of the Dutch randomised\u2010controlled trial evaluating pre\u2010treatment thiopurine S\u2010methyltransferase genotype testing (ClinicalTrials.gov <jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>00521950). Blood samples for metabolite assessment were collected at <jats:italic>T1<\/jats:italic>. Hepatotoxicity was defined by alanine aminotransaminase elevations &gt;2 times the upper normal limit or a ratio of alanine aminotransaminase\/alkaline phosphatase \u22655.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Forty\u2010seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A <jats:italic>T1<\/jats:italic> 6\u2010<jats:styled-content style=\"fixed-case\">MMPR<\/jats:styled-content> threshold of 3615 pmol\/8 \u00d7 10<jats:sup>8<\/jats:sup> erythrocytes was defined. Analysis of patients on stable thiopurine dose (<jats:italic>n<\/jats:italic> = 174) showed that those exceeding the 6\u2010<jats:styled-content style=\"fixed-case\">MMPR<\/jats:styled-content> threshold were at increased risk of hepatotoxicity: <jats:styled-content style=\"fixed-case\">OR<\/jats:styled-content> = 3.8 (95% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>: 1.8\u20138.0). Age, male gender and <jats:styled-content style=\"fixed-case\">BMI<\/jats:styled-content> were significant determinants. A predictive algorithm was developed based on these determinants and the 6\u2010<jats:styled-content style=\"fixed-case\">MMPR<\/jats:styled-content> threshold to assess hepatotoxicity risk [<jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content> = 0.83 (95% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>: 0.75\u20130.91)]. 6\u2010<jats:styled-content style=\"fixed-case\">MMPR<\/jats:styled-content> concentrations above the threshold also correlated with gastrointestinal complaints: <jats:styled-content style=\"fixed-case\">OR<\/jats:styled-content> = 2.4 (95% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>: 1.4\u20134.3), and general malaise: <jats:styled-content style=\"fixed-case\">OR<\/jats:styled-content> = 2.0 (95% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>: 1.1\u20133.7).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In more than 80% of patients, thiopurine\u2010induced hepatotoxicity could be explained by elevated <jats:italic>T1<\/jats:italic> 6\u2010<jats:styled-content style=\"fixed-case\">MMPR<\/jats:styled-content> concentrations and the independent risk factors age, gender and <jats:styled-content style=\"fixed-case\">BMI<\/jats:styled-content>, allowing personalised thiopurine treatment in <jats:styled-content style=\"fixed-case\">IBD<\/jats:styled-content> to prevent early failure.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apt.13879","type":"journal-article","created":{"date-parts":[[2016,12,12]],"date-time":"2016-12-12T00:08:08Z","timestamp":1481501288000},"page":"391-402","source":"Crossref","is-referenced-by-count":42,"title":["Early prediction of thiopurine\u2010induced hepatotoxicity in inflammatory bowel disease"],"prefix":"10.1111","volume":"45","author":[{"given":"D. R.","family":"Wong","sequence":"first","affiliation":[{"name":"Sittard\u2010Geleen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. J. H.","family":"Coenen","sequence":"additional","affiliation":[{"name":"Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. J. J.","family":"Derijks","sequence":"additional","affiliation":[{"name":"Veldhoven The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. H.","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. J.","family":"van Marrewijk","sequence":"additional","affiliation":[{"name":"Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O. H.","family":"Klungel","sequence":"additional","affiliation":[{"name":"Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Franke","sequence":"additional","affiliation":[{"name":"Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.\u2010J.","family":"Guchelaar","sequence":"additional","affiliation":[{"name":"Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. J.","family":"de Jong","sequence":"additional","affiliation":[{"name":"Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. G. J. B.","family":"Engels","sequence":"additional","affiliation":[{"name":"Sittard\u2010Geleen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. L. M.","family":"Verbeek","sequence":"additional","affiliation":[{"name":"Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. M.","family":"Hooymans","sequence":"additional","affiliation":[{"name":"Sittard\u2010Geleen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the TOPIC Recruitment Team","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,12,12]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"CD000067","article-title":"Azathioprine or 6\u2010mercaptopurine for maintenance of remission in Crohn's disease","volume":"5","author":"Chande N","year":"2015","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_7_3_1","first-page":"CD000478","article-title":"Azathioprine and 6\u2010mercaptopurine for maintenance of remission in ulcerative colitis","volume":"5","author":"Timmer A","year":"2016","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161210790112773"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ibd.21221"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/MIB.0b013e318281f28f"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2005.02636.x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2007.01187.x"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(00)70140-5"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.32420"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2003.12.001"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2004.30415.x"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.06.002"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.34"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-200406000-00016"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1258\/000456306778520070"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2003.09.017"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2007.01515.x"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra052270"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(00)80417-1"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1481803500013336"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2005.074930"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2009.04132.x"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.12511"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000312"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.025288"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.32124"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ibd.20004"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2007.03421.x"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2010.09.001"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.13559"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/ecco\u2010jcc\/jjw130"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000213"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2009.04221.x"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/ibd.23021"},{"key":"e_1_2_7_36_1","first-page":"291","article-title":"Dosing 6\u2010thioguanine in inflammatory bowel disease: expert\u2010based guidelines for daily practice","volume":"19","author":"Seinen ML","year":"2010","journal-title":"J Gastrointestin Liver Dis"}],"container-title":["Alimentary Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fapt.13879","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apt.13879","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T09:59:46Z","timestamp":1695549586000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/apt.13879"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,12]]},"references-count":35,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2017,2]]}},"alternative-id":["10.1111\/apt.13879"],"URL":"https:\/\/doi.org\/10.1111\/apt.13879","archive":["Portico"],"relation":{},"ISSN":["0269-2813","1365-2036"],"issn-type":[{"value":"0269-2813","type":"print"},{"value":"1365-2036","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,12]]}}}