{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:57:59Z","timestamp":1790927879246,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"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":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:p>\n                    Regulatory agencies request the assessment of the potential of new drugs to cause transporter\u2010mediated drug\u2010drug interactions (DDI). This assessment can be improved by integrating endogenous biomarkers during drug development. Regarding the renal excretion of drugs such as metformin, the organic cation transporter (OCT) 2 and multidrug and toxin extrusion proteins (MATE) 1 and 2\u2010K are of major importance. However, fully validated, sensitive, and specific biomarkers for these transporters are still lacking. In previous\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    studies, 5\u2010aminovaleric acid betaine (5AVAB), serotonin (5HT), and 1\u2010methylhistamine (1MH) emerged as promising biomarker candidates for OCT2\/MATE\u2010mediated DDI. Therefore, we further investigated their suitability for clinical risk assessment by evaluating the effects of the OCT2\/MATE inhibitor trimethoprim in healthy volunteers and by determining IC\n                    <jats:sub>50<\/jats:sub>\n                    values for the inhibition of OCT2\u2010 and\/or MATE1\u2010mediated uptake of the potential biomarkers by trimethoprim, cimetidine, pyrimethamine, and dolutegravir\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Trimethoprim reduced the amount excreted into urine of 5AVAB, 5HT, and 1MH\n                    <jats:italic>in vivo<\/jats:italic>\n                    by 95.1\u2009\u00b1\u20095.67%, 78.9\u2009\u00b1\u20096.56%, and 51.9\u2009\u00b1\u200914.3%, respectively (all\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001) as well as the renal clearance of 5AVAB and 5HT by 93.6\u2009\u00b1\u20095.85% and 73.8\u2009\u00b1\u200912.8%, respectively (both\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). When comparing the IC\n                    <jats:sub>50<\/jats:sub>\n                    values with unbound inhibitor plasma concentrations, trimethoprim, cimetidine, and pyrimethamine preferentially inhibit the MATE1\u2010mediated transport, whereas dolutegravir inhibits the OCT2\u2010mediated transport of the biomarker candidates. In conclusion, this study further supports the suitability of 5\u2010aminovaleric acid betaine (5AVAB), serotonin (5HT), and 1\u2010methylhistamine (1MH) as promising biomarkers for OCT2\/MATE\u2010mediated DDI.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70384","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T14:00:28Z","timestamp":1783173628000},"page":"1016-1026","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Trimethoprim on Three Previously Proposed Putative Biomarkers for\n                    <scp>OCT2<\/scp>\n                    \/\n                    <scp>MATE<\/scp>\n                    \u2010Mediated Renal Drug\u2010Drug Interactions in Healthy Volunteers"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0579-9825","authenticated-orcid":false,"given":"Jana","family":"Picurov\u00e1","sequence":"first","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0483-0293","authenticated-orcid":false,"given":"Fabian","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach an der Riss Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Auge","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7016-5482","authenticated-orcid":false,"given":"J\u00f6rg","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"FAU NeW \u2013 Research Center New Bioactive Compounds Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0334-7478","authenticated-orcid":false,"given":"Martin F.","family":"Fromm","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"FAU NeW \u2013 Research Center New Bioactive Compounds Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1729-4231","authenticated-orcid":false,"given":"Arne","family":"Gessner","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"FAU NeW \u2013 Research Center New Bioactive Compounds Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.113.007518"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1360"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00877-1"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3028"},{"key":"e_1_2_10_5_1","unstructured":"International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).ICH harmonised guideline: Drug Interaction Studies M12<https:\/\/database.ich.org\/sites\/default\/files\/ICH_M12_Step4_Guideline_2024_0521_0.pdf> (2026). 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