{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:37:09Z","timestamp":1790613429156,"version":"4.1.0"},"reference-count":23,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"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":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Irinotecan (CPT\u201011) is a prodrug of the topoisomerase I inhibitor SN\u201038 used in the treatment of metastatic carcinomas of the colon or rectum. The clinical utility of this drug is hindered by debilitating side effects, most notably, severe gastrointestinal toxicity, which affects up to 40% of patients. Although the accumulation of SN\u201038 in intestinal enterocytes, following biliary secretion and microbial metabolism of its glucuronide metabolite, is believed to be a critical preceding event to CPT\u201011\u2010induced toxicity, the transport mechanism involved in this process remains incompletely understood. Here, we tested the hypothesis that the organic anion transporting polypeptide OATP2B1 is an intestinal uptake transporter of SN\u201038 and a critical determinant of CPT\u201011\u2010induced toxicity. Mice with Oatp2b1 deficiency experienced milder diarrhea and reduced changes in their intestine length, a known injury marker, compared to wild\u2010type mice when subjected to CPT\u201011 treatment. These observations were confirmed by a histological examination indicating that damage to intestinal enterocytes was more severe in wild\u2010type mice. The phenotypic alterations in Oatp2b1\u2010deficient mice occurred without substantial changes in measures of systemic exposure to the parent drug, SN\u201038, or its glucuronide conjugate. Collectively, our study indicates that plasma concentrations of SN\u201038 are a poor predictive biomarker of CPT\u201011\u2010induced gastrointestinal toxicity and provides an incentive for the future development of intervention strategies aimed at increasing the tolerance to this clinically important drug with the use of OATP2B1 inhibitors.<\/jats:p>","DOI":"10.1111\/cts.70452","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T05:24:58Z","timestamp":1767072298000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>OATP2B1<\/scp>\n                    Deficiency Ameliorates Irinotecan\u2010Induced Gastrointestinal Toxicity"],"prefix":"10.1111","volume":"19","author":[{"given":"Hanieh","family":"Taheri","sequence":"first","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology College of Pharmacy, the Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"de Bruijn","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Erasmus University Medical Center  Rotterdam GD the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology College of Pharmacy, the Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas R.","family":"Kleinert","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology College of Pharmacy, the Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara N.","family":"Corps","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences College of Veterinary Medicine, the Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5667-5697","authenticated-orcid":false,"given":"Ron H. J.","family":"Mathijssen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Erasmus University Medical Center  Rotterdam GD the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6561-3295","authenticated-orcid":false,"given":"Kevin M.","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology College of Pharmacy, the Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2660-6644","authenticated-orcid":false,"given":"Alex","family":"Sparreboom","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology College of Pharmacy, the Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9806-7734","authenticated-orcid":false,"given":"Shuiying","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology College of Pharmacy, the Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2024.176614"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph18030359"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1319123110"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.121.000644"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.06.004"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0330"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2011.519"},{"issue":"8","key":"e_1_2_10_9_1","first-page":"2182","article-title":"Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT\u201011)","volume":"7","author":"Mathijssen R. 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