{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T09:14:40Z","timestamp":1777799680544,"version":"3.51.4"},"reference-count":45,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T00:00:00Z","timestamp":1752192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Netherlands Organisation for Scientific Research, NWO (Applied and Engineering Sciences domain)","award":["19060"],"award-info":[{"award-number":["19060"]}]},{"name":"Netherlands Organisation for Scientific Research, NWO (Applied and Engineering Sciences domain)","award":["TransplantLines Biobank and Cohort Study"],"award-info":[{"award-number":["TransplantLines Biobank and Cohort Study"]}]},{"name":"Netherlands Organisation for Scientific Research, NWO (Applied and Engineering Sciences domain)","award":["PA-SP\/PRJ-2020-9136"],"award-info":[{"award-number":["PA-SP\/PRJ-2020-9136"]}]},{"name":"Netherlands Organisation for Scientific Research, NWO (Applied and Engineering Sciences domain)","award":["14939"],"award-info":[{"award-number":["14939"]}]},{"name":"Netherlands Organisation for Scientific Research, NWO (Applied and Engineering Sciences domain)","award":["PPP-2019-032"],"award-info":[{"award-number":["PPP-2019-032"]}]},{"name":"Netherlands Organisation for Scientific Research, NWO (Applied and Engineering Sciences domain)","award":["PPP-2022-015"],"award-info":[{"award-number":["PPP-2022-015"]}]},{"name":"Astellas BV","award":["19060"],"award-info":[{"award-number":["19060"]}]},{"name":"Astellas BV","award":["TransplantLines Biobank and Cohort Study"],"award-info":[{"award-number":["TransplantLines Biobank and Cohort Study"]}]},{"name":"Astellas BV","award":["PA-SP\/PRJ-2020-9136"],"award-info":[{"award-number":["PA-SP\/PRJ-2020-9136"]}]},{"name":"Astellas BV","award":["14939"],"award-info":[{"award-number":["14939"]}]},{"name":"Astellas BV","award":["PPP-2019-032"],"award-info":[{"award-number":["PPP-2019-032"]}]},{"name":"Astellas BV","award":["PPP-2022-015"],"award-info":[{"award-number":["PPP-2022-015"]}]},{"name":"Chiesi Pharmaceuticals BV","award":["19060"],"award-info":[{"award-number":["19060"]}]},{"name":"Chiesi Pharmaceuticals BV","award":["TransplantLines Biobank and Cohort Study"],"award-info":[{"award-number":["TransplantLines Biobank and Cohort Study"]}]},{"name":"Chiesi Pharmaceuticals BV","award":["PA-SP\/PRJ-2020-9136"],"award-info":[{"award-number":["PA-SP\/PRJ-2020-9136"]}]},{"name":"Chiesi Pharmaceuticals BV","award":["14939"],"award-info":[{"award-number":["14939"]}]},{"name":"Chiesi Pharmaceuticals BV","award":["PPP-2019-032"],"award-info":[{"award-number":["PPP-2019-032"]}]},{"name":"Chiesi Pharmaceuticals BV","award":["PPP-2022-015"],"award-info":[{"award-number":["PPP-2022-015"]}]},{"name":"NWO\/TTW via a partnership program with DSM Animal Nutrition and Health, the Netherlands","award":["19060"],"award-info":[{"award-number":["19060"]}]},{"name":"NWO\/TTW via a partnership program with DSM Animal Nutrition and Health, the Netherlands","award":["TransplantLines Biobank and Cohort Study"],"award-info":[{"award-number":["TransplantLines Biobank and Cohort Study"]}]},{"name":"NWO\/TTW via a partnership program with DSM Animal Nutrition and Health, the Netherlands","award":["PA-SP\/PRJ-2020-9136"],"award-info":[{"award-number":["PA-SP\/PRJ-2020-9136"]}]},{"name":"NWO\/TTW via a partnership program with DSM Animal Nutrition and Health, the Netherlands","award":["14939"],"award-info":[{"award-number":["14939"]}]},{"name":"NWO\/TTW via a partnership program with DSM Animal Nutrition and Health, the Netherlands","award":["PPP-2019-032"],"award-info":[{"award-number":["PPP-2019-032"]}]},{"name":"NWO\/TTW via a partnership program with DSM Animal Nutrition and Health, the Netherlands","award":["PPP-2022-015"],"award-info":[{"award-number":["PPP-2022-015"]}]},{"name":"Dutch Ministry of Economic Affairs and Climate Policy by means of so-called PPP allowances, made available by the Top Sector Life Sciences &amp; Health to stimulate public\u2013private partnerships","award":["19060"],"award-info":[{"award-number":["19060"]}]},{"name":"Dutch Ministry of Economic Affairs and Climate Policy by means of so-called PPP allowances, made available by the Top Sector Life Sciences &amp; Health to stimulate public\u2013private partnerships","award":["TransplantLines Biobank and Cohort Study"],"award-info":[{"award-number":["TransplantLines Biobank and Cohort Study"]}]},{"name":"Dutch Ministry of Economic Affairs and Climate Policy by means of so-called PPP allowances, made available by the Top Sector Life Sciences &amp; Health to stimulate public\u2013private partnerships","award":["PA-SP\/PRJ-2020-9136"],"award-info":[{"award-number":["PA-SP\/PRJ-2020-9136"]}]},{"name":"Dutch Ministry of Economic Affairs and Climate Policy by means of so-called PPP allowances, made available by the Top Sector Life Sciences &amp; Health to stimulate public\u2013private partnerships","award":["14939"],"award-info":[{"award-number":["14939"]}]},{"name":"Dutch Ministry of Economic Affairs and Climate Policy by means of so-called PPP allowances, made available by the Top Sector Life Sciences &amp; Health to stimulate public\u2013private partnerships","award":["PPP-2019-032"],"award-info":[{"award-number":["PPP-2019-032"]}]},{"name":"Dutch Ministry of Economic Affairs and Climate Policy by means of so-called PPP allowances, made available by the Top Sector Life Sciences &amp; Health to stimulate public\u2013private partnerships","award":["PPP-2022-015"],"award-info":[{"award-number":["PPP-2022-015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: The increased use of antibiotics is raising concerns about environmental contamination and antibiotic resistance, exemplified by the case of cotrimoxazole, a widely prescribed combination of sulfamethoxazole and trimethoprim. After oral administration and absorption, both drugs are excreted in their parent and metabolized forms, which is a factor that is commonly considered in environmental studies. Many studies, however, rely on pharmacokinetic data from drug developers, who mostly investigate drug metabolism in healthy male volunteers rather than in actual patient populations. Methods: We investigated the real-world metabolism and urinary excretion of cotrimoxazole in an LC-SWATH\/MS-based pharmacometabolomics study of 149 kidney transplant recipients who took part in the TransplantLines Biobank and Cohort Study (NCT0327284). Results: Our study confirmed (as \u201cputatively characterized compound classes\u201d) the presence of all the expected metabolites, and we (putatively) identified several previously unreported metabolites, including glucuronide conjugates of both drugs and two isoxazole ring-opened variants of sulfamethoxazole. The relative metabolite profiles furthermore indicated that the active drug trimethoprim accounted for 75% of the total signal intensity. For sulfamethoxazole, its acetylated metabolite was the main metabolite (59%), followed by the active parent drug (17%) and its glucuronide (7%). Alongside trimethoprim, these substances could serve as analytical targets for environmental cotrimoxazole monitoring, given their abundance (all three substances), activity (parent drug), and\/or back-transformation potential (both conjugated metabolites). The isoxazole ring-opened variants (2\u20133%) may also warrant attention, considering their (presumed) absolute excreted quantities and potential pharmacological activity. Conclusions: This study underscores the value of pharmacometabolomics in elucidating real-world metabolite profiles, and it provides novel insights into cotrimoxazole metabolism and excretion, with implications for environmental and clinical monitoring.<\/jats:p>","DOI":"10.3390\/metabo15070473","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T10:26:53Z","timestamp":1752229613000},"page":"473","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacometabolomics Study of Sulfamethoxazole and Trimethoprim in Kidney Transplant Recipients: Real-World Metabolism and Urinary Excretion"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5769-1522","authenticated-orcid":false,"given":"Marieke A. J.","family":"Hof","sequence":"first","affiliation":[{"name":"Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hessel","family":"de Haan","sequence":"additional","affiliation":[{"name":"Unit of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stepan","family":"Stepanovic","sequence":"additional","affiliation":[{"name":"Life Sciences Mass Spectrometry, Department of Inorganic and Analytical Chemistry, University of Geneva, Quai Ernest Ansermet 24, 1211 Gen\u00e8ve, Switzerland"},{"name":"Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njego\u0161eva 12, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3356-6791","authenticated-orcid":false,"given":"Stephan J. L.","family":"Bakker","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eelko","family":"Hak","sequence":"additional","affiliation":[{"name":"Unit of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00e9rard","family":"Hopfgartner","sequence":"additional","affiliation":[{"name":"Life Sciences Mass Spectrometry, Department of Inorganic and Analytical Chemistry, University of Geneva, Quai Ernest Ansermet 24, 1211 Gen\u00e8ve, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3503-1694","authenticated-orcid":false,"given":"Frank","family":"Klont","sequence":"additional","affiliation":[{"name":"Unit of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"},{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"TransplantLines","family":"Investigators","sequence":"additional","affiliation":[{"name":"Group of Authors on Behalf of the Transplant Lines Biobank and Cohort Study, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,11]]},"reference":[{"key":"ref_1","first-page":"259","article-title":"Greening the Pharmacy","volume":"377","author":"Orive","year":"2022","journal-title":"Science (1979)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"108524","DOI":"10.1016\/j.envint.2024.108524","article-title":"Assessing City-Wide Pharmaceutical Emissions to Wastewater via Modelling and Passive Sampling","volume":"185","author":"Zillien","year":"2024","journal-title":"Environ. 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