{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:14:06Z","timestamp":1792019646708,"version":"4.4.0"},"reference-count":73,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T00:00:00Z","timestamp":1774051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Netherlands Organisation for Scientific Research, NWO","award":["19060"],"award-info":[{"award-number":["19060"]}]},{"name":"Astellas BV (project code: TransplantLines Biobank and Cohort Study), Chiesi Pharmaceuticals BV","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"]}]},{"DOI":"10.13039\/501100016238","name":"Dutch Ministry of Economic Affairs and Climate Policy","doi-asserted-by":"crossref","award":["PPP-2019-032"],"award-info":[{"award-number":["PPP-2019-032"]}],"id":[{"id":"10.13039\/501100016238","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100016238","name":"Dutch Ministry of Economic Affairs and Climate Policy","doi-asserted-by":"crossref","award":["PPP-2022-015"],"award-info":[{"award-number":["PPP-2022-015"]}],"id":[{"id":"10.13039\/501100016238","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Clopidogrel is a widely prescribed antiplatelet prodrug that requires bioactivation, primarily by the polymorphic CYP2C19 enzyme. Genetic variation in this enzyme leads to differences in active metabolite formation and has prompted the development of pharmacogenetics-guided prescribing. However, current pharmacogenetic strategies are grounded in drug metabolism knowledge derived from mass balance studies conducted in small groups of healthy volunteers. This narrow evidence base may limit the data\u2019s applicability to real-world settings, where factors like polypharmacy or altered organ function may influence drug response. Methods: Pharmacogenetics could benefit from real-world drug metabolism and excretion studies, which we conducted for clopidogrel in 38 kidney and 16 liver transplant recipients from the TransplantLines Biobank and Cohort Study (NCT03272841), utilizing existing LC-SWATH\/MS pharmacometabolomic data. Clopidogrel-associated metabolic signals were identified using xenobiotic metabolism knowledge and literature-reported pathways. Results: Across both transplant groups, 26 clopidogrel-associated features were prioritized, of which some matched previously reported urinary metabolites, had previously been observed in plasma, or represented previously unreported metabolites. Clopidogrel carboxylic acid predominated in kidney transplant recipients, whereas its glucuronide form was most abundant in liver transplant recipients. Notably, unmetabolized clopidogrel was consistently detected across all patients. Moreover, our data support a thiol desulfurization route, aligning with emerging evidence of clopidogrel\u2019s role as a hydrogen sulfide-releasing drug. Conclusions: More (putative) clopidogrel metabolites were detected than previously reported, demonstrating the value of pharmacometabolomics in expanding our understanding of drug metabolism. This approach provides novel data that may complement pharmacogenetics research to understand clopidogrel response variability among treated patients.<\/jats:p>","DOI":"10.3390\/metabo16030210","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:48:42Z","timestamp":1774259322000},"page":"210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacometabolomics Detects Unreported Clopidogrel Metabolites in the Urine of Kidney and Liver Transplant Recipients"],"prefix":"10.3390","volume":"16","author":[{"given":"Cassandra","family":"Piccolotto","sequence":"first","affiliation":[{"name":"Unit of Pharmaco Therapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7900-5917","authenticated-orcid":false,"given":"Vincent E.","family":"de Meijer","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 30, 1211 Gen\u00e8ve, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Fodran","sequence":"additional","affiliation":[{"name":"Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3503-1694","authenticated-orcid":false,"given":"Frank","family":"Klont","sequence":"additional","affiliation":[{"name":"Unit of Pharmaco Therapy, 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":[{"vocabulary":"crossref","role":"author"}]},{"given":"TransplantLines Investigators","family":"TransplantLines 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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"ref_1","first-page":"425","article-title":"Personalised MEDICINE: Implication and Perspectives in the Field of Occupational Health","volume":"111","author":"Bollati","year":"2020","journal-title":"Med. 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