{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:33:28Z","timestamp":1791812008431,"version":"4.3.4"},"reference-count":29,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T00:00:00Z","timestamp":1651622400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:p>\n                    In clinical practice, 25\u201330% of the patients treated with fluoropyrimidines experience severe fluoropyrimidine\u2010related toxicity. Extensively clinically validated\n                    <jats:italic>DPYD<\/jats:italic>\n                    genotyping tests are available to identify patients at risk of severe toxicity due to decreased activity of dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme in fluoropyrimidine metabolism. In April 2020, the European Medicines Agency recommended that, as an alternative for\n                    <jats:italic>DPYD<\/jats:italic>\n                    genotype\u2010based testing for DPD deficiency, also phenotype testing based on pretreatment plasma uracil levels is a suitable method to identify patients with DPD deficiency. Although the evidence for genotype\u2010directed dosing of fluoropyrimidines is substantial, the level of evidence supporting plasma uracil levels to predict DPD activity in clinical practice is limited. Notwithstanding this, uracil\u2010based phenotyping is now used in clinical practice in various countries in Europe. We aimed to determine the value of pretreatment uracil levels in predicting DPD deficiency and severe treatment\u2010related toxicity. To this end, we determined pretreatment uracil levels in 955 patients with cancer, and assessed the correlation with DPD activity in peripheral blood mononuclear cells (PBMCs) and fluoropyrimidine\u2010related severe toxicity. We identified substantial issues concerning the use of pretreatment uracil in clinical practice, including large between\u2010center study differences in measured pretreatment uracil levels, most likely as a result of pre\u2010analytical factors. Importantly, we were not able to correlate pretreatment uracil levels with DPD activity nor were uracil levels predictive of severe treatment\u2010related toxicity. We urge that robust clinical validation should first be performed before pretreatment plasma uracil levels are used in clinical practice as part of a dosing strategy for fluoropyrimidines.\n                  <\/jats:p>","DOI":"10.1002\/cpt.2608","type":"journal-article","created":{"date-parts":[[2022,4,9]],"date-time":"2022-04-09T14:55:34Z","timestamp":1649516134000},"page":"62-68","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Dihydropyrimidine Dehydrogenase Phenotyping Using Pretreatment Uracil: A Note of Caution Based on a Large Prospective Clinical Study"],"prefix":"10.1111","volume":"112","author":[{"given":"Mirjam","family":"de With","sequence":"first","affiliation":[{"name":"Department of Medical Oncology Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"},{"name":"Department of Clinical Chemistry Erasmus Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Knikman","sequence":"additional","affiliation":[{"name":"Division of Pharmacology The Netherlands Cancer Institute Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Femke M.","family":"de Man","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carin A. T. C.","family":"Lunenburg","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda M.","family":"Henricks","sequence":"additional","affiliation":[{"name":"Division of Pharmacology The Netherlands Cancer Institute Amsterdam The Netherlands"},{"name":"Division of Medical Oncology Department of Clinical Pharmacology The Netherlands Cancer Institute Amsterdam The Netherlands"},{"name":"Department of Clinical Chemistry and Laboratory Medicine Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 B. P.","family":"van Kuilenburg","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases Department of Clinical Chemistry Amsterdam UMC Cancer Center Amsterdam Amsterdam Gastroenterology Endocrinology Metabolism University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan G.","family":"Maring","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Isala Hospital Zwolle The Netherlands"},{"name":"Isala Diaconessen Hospital Meppel The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice C.","family":"van Staveren","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Treant Healthgroup Scheper Hospital Emmen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Rosing","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos H.","family":"Beijnen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute Amsterdam The Netherlands"},{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Department of Pharmaceutical Sciences Faculty of Science Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dick","family":"Pluim","sequence":"additional","affiliation":[{"name":"Division of Pharmacology The Netherlands Cancer Institute Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil","family":"Modak","sequence":"additional","affiliation":[{"name":"Cambridge Isotope Laboratories Tewksbury Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex L. T.","family":"Imholz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Deventer Hospital Deventer The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron H. N.","family":"van Schaik","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Erasmus Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan H. M.","family":"Schellens","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Department of Pharmaceutical Sciences Faculty of Science Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Gelderblom","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke","family":"Cats","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology Department of Gastrointestinal Oncology The Netherlands Cancer Institute Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk\u2010Jan","family":"Guchelaar","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands"},{"name":"Leiden Network for Personalised Therapeutics (LNPT) Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron H. J.","family":"Mathijssen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse J.","family":"Swen","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands"},{"name":"Leiden Network for Personalised Therapeutics (LNPT) Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Meulendijks","sequence":"additional","affiliation":[{"name":"Division of Pharmacology The Netherlands Cancer Institute Amsterdam The Netherlands"},{"name":"Division of Medical Oncology Department of Clinical Pharmacology The Netherlands Cancer Institute Amsterdam The Netherlands"},{"name":"Late Development Oncology AstraZeneca Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)00286-7"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2001.19.8.2282"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61086-1"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2001.19.21.4097"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/onco.13967"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2019.09.028"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.63.1325"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/tpj.2013.25"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2069"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.51.1857"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.13.116"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30686-7"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2018.11.010"},{"key":"e_1_2_10_15_1","unstructured":"Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA).Assessment report: Fluorouracil and fluorouracil related substances (capecitabine tegafur and flucytosine) containing medicinal products<https:\/\/www.ema.europa.eu\/en\/documents\/referral\/fluorouracil\u2010fluorouracil\u2010related\u2010substances\u2010article\u201031\u2010referral\u2010assessment\u2010report_en.pdf> (2020). Accessed August 11 2021."},{"key":"e_1_2_10_16_1","unstructured":"European Medicines Agency (EMA).EMA recommendations on DPD testing prior to treatment with fluorouracil capecitabine tegafur and flucytosine<https:\/\/www.ema.europa.eu\/en\/news\/ema\u2010recommendations\u2010dpd\u2010testing\u2010prior\u2010treatment\u2010fluorouracil\u2010capecitabine\u2010tegafur\u2010flucytosine> (2020). Accessed September 13 2021."},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2006.09.006"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.94"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175998"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.14.126"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/chromsci\/bms085"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2016.04.039"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/46.1.9"},{"key":"e_1_2_10_24_1","unstructured":"NCI.National Cancer Institute: Common Terminology Criteria for Adverse Events v4.03<https:\/\/evs.NCI.nih.gov\/ftp1\/CTCAE\/CTCAE_4.03\/CTCAE_4.03_2010\u201006\u201014_QuickReference_8.5x11.pdf> (2010). Accessed August 2021."},{"key":"e_1_2_10_25_1","first-page":"4705","article-title":"Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5\u2010fluorouracil\u2010associated toxicity: identification of new mutations in the DPD gene","volume":"6","author":"Kuilenburg A.B.","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2021-0921"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13007"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/17843286.2020.1870855"},{"key":"e_1_2_10_29_1","unstructured":"Haute Autorit\u00e9 de Sant\u00e9.Des recommandations pour pr\u00e9venir certaines toxicit\u00e9s s\u00e9v\u00e8res des chimioth\u00e9rapies par fluoropyrimidines<https:\/\/www.has\u2010sante.fr\/jcms\/c_2892234\/fr\/des\u2010recommandations\u2010pour\u2010prevenir\u2010certaines\u2010toxicites\u2010severes\u2010des\u2010chimiotherapies\u2010par\u2010fluoropyrimidines> (2018). 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