{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:24:51Z","timestamp":1792783491168,"version":"4.5.0"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"},{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"funder":[{"name":"The Swedish Cancer Society","award":["CAN 201025 PjF"],"award-info":[{"award-number":["CAN 201025 PjF"]}],"id":[{"id":"https:\/\/ror.org\/0527jb766","id-type":"ROR","asserted-by":"crossref"}]},{"name":"The Swedish Cancer Society","award":["CAN 222370 Pj01"],"award-info":[{"award-number":["CAN 222370 Pj01"]}],"id":[{"id":"https:\/\/ror.org\/0527jb766","id-type":"ROR","asserted-by":"crossref"}]},{"name":"The King Gustav V Jubilee Clinic Foundation for Cancer Research","award":["2016:70"],"award-info":[{"award-number":["2016:70"]}],"id":[{"id":"https:\/\/ror.org\/00kbbk236","id-type":"ROR","asserted-by":"crossref"}]},{"name":"The Swedish State under the LUA\/ALF agreement","award":["ALFGBG-723361"],"award-info":[{"award-number":["ALFGBG-723361"]}]},{"name":"The Swedish State under the LUA\/ALF agreement","award":["ALFGBG-966007"],"award-info":[{"award-number":["ALFGBG-966007"]}]},{"name":"The IngaBritt and Arne Lundberg Foundation","award":["335\/07"],"award-info":[{"award-number":["335\/07"]}]},{"name":"University of Gothenburg","id":[{"id":"https:\/\/ror.org\/01tm6cn81","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Drug Metab Pharmacokinet"],"DOI":"10.1007\/s13318-026-01039-5","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T09:16:10Z","timestamp":1789809370000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Alterations in Blood and Saliva During the First Two Cycles of Adjuvant Chemotherapy Correlate with 5-FU Dose Reduction Requirement in Patients with Colorectal Cancer"],"prefix":"10.1007","author":[{"given":"G\u00f6ran","family":"Carlsson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Odin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bengt","family":"Gustavsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8660-7169","authenticated-orcid":false,"given":"Yvonne","family":"Wettergren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"issue":"4","key":"1039_CR1","first-page":"E499","volume":"65","author":"D Darmadi","year":"2024","unstructured":"Darmadi D, Mohammadian-Hafshejani A, Kheiri S. Global disparities in colorectal cancer: unveiling the present landscape of incidence and mortality rates, analyzing geographical variances, and assessing the Human Development Index. J Prev Med Hyg. 2024;65(4):E499\u2013514.","journal-title":"J Prev Med Hyg"},{"issue":"8","key":"1039_CR2","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1016\/0277-5379(90)90188-Y","volume":"26","author":"G Carlsson","year":"1990","unstructured":"Carlsson G, et al. Sequential 5-fluorouracil and leucovorin in patients with advanced symptomatic gastrointestinal cancer. Eur J Cancer. 1990;26(8):874\u20136.","journal-title":"Eur J Cancer"},{"issue":"15","key":"1039_CR3","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1200\/JCO.2011.38.0915","volume":"30","author":"KM Tveit","year":"2012","unstructured":"Tveit KM, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012;30(15):1755\u201362.","journal-title":"J Clin Oncol"},{"issue":"4","key":"1039_CR4","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1007\/s00280-014-2553-2","volume":"74","author":"G Carlsson","year":"2014","unstructured":"Carlsson G, et al. Pretherapeutic uracil and dihydrouracil levels in saliva of colorectal cancer patients are associated with toxicity during adjuvant 5-fluorouracil-based chemotherapy. Cancer Chemother Pharmacol. 2014;74(4):757\u201363.","journal-title":"Cancer Chemother Pharmacol"},{"issue":"11","key":"1039_CR5","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1093\/annonc\/mdl284","volume":"17","author":"M Gusella","year":"2006","unstructured":"Gusella M, et al. Pharmacokinetic and demographic markers of 5-fluorouracil toxicity in 181 patients on adjuvant therapy for colorectal cancer. Ann Oncol. 2006;17(11):1656\u201360.","journal-title":"Ann Oncol"},{"issue":"9","key":"1039_CR6","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.clon.2006.08.005","volume":"18","author":"VS Ramani","year":"2006","unstructured":"Ramani VS, Gollins SW, Wong H. Weekly fluorouracil at 425 mg\/m2 plus low-dose folinic acid for 24 weeks as adjuvant treatment for colorectal cancer: assessment of toxicity and delivery. Clin Oncol (R Coll Radiol). 2006;18(9):649\u201357.","journal-title":"Clin Oncol (R Coll Radiol)"},{"issue":"1","key":"1039_CR7","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s00280-020-04173-2","volume":"87","author":"H Taflin","year":"2021","unstructured":"Taflin H, et al. Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin. Cancer Chemother Pharmacol. 2021;87(1):31\u201341.","journal-title":"Cancer Chemother Pharmacol"},{"issue":"11","key":"1039_CR8","doi-asserted-by":"publisher","first-page":"2935","DOI":"10.1002\/cncr.26595","volume":"118","author":"Y Wettergren","year":"2012","unstructured":"Wettergren Y, et al. Pretherapeutic uracil and dihydrouracil levels of colorectal cancer patients are associated with sex and toxic side effects during adjuvant 5-fluorouracil-based chemotherapy. Cancer. 2012;118(11):2935\u201343.","journal-title":"Cancer"},{"issue":"1","key":"1039_CR9","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/1097-0142(19950101)75:1<11::AID-CNCR2820750104>3.0.CO;2-N","volume":"75","author":"BN Stein","year":"1995","unstructured":"Stein BN, et al. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer. 1995;75(1):11\u20137.","journal-title":"Cancer"},{"issue":"1","key":"1039_CR10","first-page":"27","volume":"68","author":"M Boisdron-Celle","year":"2010","unstructured":"Boisdron-Celle M, Morel A, Gamelin E. Dihydropyrimidine dehydrogenase deficiency and toxicity to fluoropyrimidine. Ann Biol Clin (Paris). 2010;68(1):27\u201332.","journal-title":"Ann Biol Clin (Paris)"},{"issue":"4","key":"1039_CR11","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1023\/A:1006416410198","volume":"18","author":"JL Grem","year":"2000","unstructured":"Grem JL. 5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. Investig New Drugs. 2000;18(4):299\u2013313.","journal-title":"Investig New Drugs"},{"issue":"5","key":"1039_CR12","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1038\/s41416-023-02517-2","volume":"130","author":"G Le Teuff","year":"2024","unstructured":"Le Teuff G, et al. Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis. Br J Cancer. 2024;130(5):808\u201318.","journal-title":"Br J Cancer"},{"key":"1039_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2023.104061","volume":"188","author":"NRK Zwart","year":"2023","unstructured":"Zwart NRK, et al. Folate, folic acid, and chemotherapy-induced toxicities: a systematic literature review. Crit Rev Oncol Hematol. 2023;188:104061.","journal-title":"Crit Rev Oncol Hematol"},{"key":"1039_CR14","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s12986-017-0233-z","volume":"14","author":"A Kumar","year":"2017","unstructured":"Kumar A, et al. The metabolism and significance of homocysteine in nutrition and health. Nutr Metab (Lond). 2017;14:78.","journal-title":"Nutr Metab (Lond)"},{"issue":"2","key":"1039_CR15","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1177\/1721727X0300100205","volume":"1","author":"M Palasopoulou","year":"2003","unstructured":"Palasopoulou M, Haitoglou C, Papageorgiou G, Dimitriadou A. PLP Induced inhibition of thymidylate synthase activity in T lymphocytes. Eur J Inflamm. 2003;1(2):79\u201383.","journal-title":"Eur J Inflamm"},{"key":"1039_CR16","doi-asserted-by":"publisher","DOI":"10.3390\/nu13093229","author":"K Stach","year":"2021","unstructured":"Stach K, Stach W, Augoff K. Vitamin B6 in health and disease. Nutrients. 2021. https:\/\/doi.org\/10.3390\/nu13093229.","journal-title":"Nutrients"},{"key":"1039_CR17","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics11050199","author":"TJ Wigle","year":"2019","unstructured":"Wigle TJ, et al. DPYD and fluorouracil-based chemotherapy: mini review and case report. Pharmaceutics. 2019. https:\/\/doi.org\/10.3390\/pharmaceutics11050199.","journal-title":"Pharmaceutics"},{"issue":"1","key":"1039_CR18","doi-asserted-by":"publisher","first-page":"39","DOI":"10.2217\/pme-2022-0042","volume":"20","author":"P Sivamani","year":"2023","unstructured":"Sivamani P, et al. Identification of DPYD variants and estimation of uracil and dihydrouracil in a healthy Indian population. Per Med. 2023;20(1):39\u201353.","journal-title":"Per Med"},{"issue":"1","key":"1039_CR19","first-page":"103","volume":"8","author":"HE Ford","year":"2002","unstructured":"Ford HE, et al. Patterns of elevation of plasma 2'-deoxyuridine, a surrogate marker of thymidylate synthase (TS) inhibition, after administration of two different schedules of 5-fluorouracil and the specific TS inhibitors raltitrexed (Tomudex) and ZD9331. Clin Cancer Res. 2002;8(1):103\u20139.","journal-title":"Clin Cancer Res"},{"key":"1039_CR20","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15010258","author":"H Taflin","year":"2022","unstructured":"Taflin H, et al. Increasing dosage of leucovorin results in pharmacokinetic and gene expression differences when administered as two-hour infusion or bolus injection to patients with colon cancer. Cancers (Basel). 2022. https:\/\/doi.org\/10.3390\/cancers15010258.","journal-title":"Cancers (Basel)"},{"issue":"2","key":"1039_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-019-0216-4","volume":"51","author":"T Hasan","year":"2019","unstructured":"Hasan T, et al. Disturbed homocysteine metabolism is associated with cancer. Exp Mol Med. 2019;51(2):1\u201313.","journal-title":"Exp Mol Med"},{"issue":"9","key":"1039_CR22","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1093\/eurjpc\/zwae022","volume":"31","author":"DF Wu","year":"2024","unstructured":"Wu DF, Yin RX, Deng JL. Homocysteine, hyperhomocysteinemia, and H-type hypertension. Eur J Prev Cardiol. 2024;31(9):1092\u2013103.","journal-title":"Eur J Prev Cardiol"},{"issue":"4","key":"1039_CR23","first-page":"238","volume":"10","author":"AS Lucas","year":"2011","unstructured":"Lucas AS, O\u2019Neil BH, Goldberg RM. A decade of advances in cytotoxic chemotherapy for metastatic colorectal cancer. Clin Colorectal Cancer. 2011;10(4):238\u201344.","journal-title":"Clin Colorectal Cancer"},{"issue":"5","key":"1039_CR24","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1097\/CAD.0000000000000220","volume":"26","author":"H Tanaka","year":"2015","unstructured":"Tanaka H, et al. Plasma homocysteine levels and hematological toxicity in NSCLC patients after the first cycle of pemetrexed under folate supplementation. Anticancer Drugs. 2015;26(5):573\u20138.","journal-title":"Anticancer Drugs"},{"issue":"4","key":"1039_CR25","doi-asserted-by":"publisher","DOI":"10.2174\/1573403X19666230209111854","volume":"19","author":"A Mohan","year":"2023","unstructured":"Mohan A, et al. Homocysteine, vitamin B12 and folate level: possible risk factors in the progression of chronic heart and kidney disorders. Curr Cardiol Rev. 2023;19(4):e090223213539.","journal-title":"Curr Cardiol Rev"},{"issue":"2","key":"1039_CR26","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.ajcnut.2025.05.029","volume":"122","author":"AK Bozack","year":"2025","unstructured":"Bozack AK, et al. One-carbon metabolism-related compounds are associated with epigenetic aging biomarkers: results from the cross-sectional National Health and Nutrition Examination Survey 1999\u20132002. Am J Clin Nutr. 2025;122(2):413\u201323.","journal-title":"Am J Clin Nutr"},{"key":"1039_CR27","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.arr.2018.10.010","volume":"49","author":"EA Ostrakhovitch","year":"2019","unstructured":"Ostrakhovitch EA, Tabibzadeh S. Homocysteine and age-associated disorders. Ageing Res Rev. 2019;49:144\u201364.","journal-title":"Ageing Res Rev"},{"key":"1039_CR28","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14092998","author":"J Sirivarasai","year":"2025","unstructured":"Sirivarasai J, et al. Association between plasma homocysteine, folate, vitamin B12 levels, and metabolic dysfunction indices in elderly with arterial stiffness. J Clin Med. 2025. https:\/\/doi.org\/10.3390\/jcm14092998.","journal-title":"J Clin Med"},{"issue":"9","key":"1039_CR29","first-page":"2125","volume":"4","author":"J Geisler","year":"1998","unstructured":"Geisler J, et al. Changes in folate status as determined by reduction in total plasma homocysteine levels during leucovorin modulation of 5-fluorouracil therapy in cancer patients. Clin Cancer Res. 1998;4(9):2125\u20138.","journal-title":"Clin Cancer Res"},{"issue":"3","key":"1039_CR30","doi-asserted-by":"publisher","first-page":"153","DOI":"10.5152\/UCD.2014.2653","volume":"30","author":"T Simsek","year":"2014","unstructured":"Simsek T, Simsek HU, Canturk NZ. Response to trauma and metabolic changes: posttraumatic metabolism. Turk J Surg. 2014;30(3):153\u20139.","journal-title":"Turk J Surg"},{"issue":"11","key":"1039_CR31","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1038\/bjc.2017.94","volume":"116","author":"D Meulendijks","year":"2017","unstructured":"Meulendijks D, et al. Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity. Br J Cancer. 2017;116(11):1415\u201324.","journal-title":"Br J Cancer"},{"key":"1039_CR32","doi-asserted-by":"publisher","DOI":"10.3390\/ph18050653","author":"H Mielke","year":"2025","unstructured":"Mielke H, Algharably EAE, Gundert-Remy U. 5-Fluorouracil toxicity: revisiting the relevance of pharmacokinetic parameters. Pharmaceuticals (Basel). 2025. https:\/\/doi.org\/10.3390\/ph18050653.","journal-title":"Pharmaceuticals (Basel)"},{"issue":"1","key":"1039_CR33","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1007\/s00280-025-04851-z","volume":"95","author":"GA Brooks","year":"2025","unstructured":"Brooks GA, et al. Association of DPYD rs4294451, plasma uracil concentration, and sex with 5-fluorouracil exposure in patients with gastrointestinal cancer. Cancer Chemother Pharmacol. 2025;95(1):120.","journal-title":"Cancer Chemother Pharmacol"},{"issue":"12","key":"1039_CR34","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2024.104002","volume":"9","author":"J Delahousse","year":"2024","unstructured":"Delahousse J, et al. Sex differences in the pharmacokinetics of anticancer drugs: a systematic review. ESMO Open. 2024;9(12):104002.","journal-title":"ESMO Open"}],"container-title":["European Journal of Drug Metabolism and Pharmacokinetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13318-026-01039-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s13318-026-01039-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13318-026-01039-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T09:16:13Z","timestamp":1789809373000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s13318-026-01039-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,19]]},"references-count":34,"alternative-id":["1039"],"URL":"https:\/\/doi.org\/10.1007\/s13318-026-01039-5","relation":{},"ISSN":["0378-7966","2107-0180"],"issn-type":[{"value":"0378-7966","type":"print"},{"value":"2107-0180","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,19]]},"assertion":[{"value":"6 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors have no conflicts of interests to declare that are relevant to the content of this article.","order":1,"name":"Ethics","label":"Conflict of Interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the regional ethical review board in Gothenburg (no. 118-15).","order":2,"name":"Ethics","label":"Ethical Approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Written informed consent was obtained from all patients prior to participation.","order":3,"name":"Ethics","label":"Consent to Participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable","order":4,"name":"Ethics","label":"Consent for Publication","group":{"name":"EthicsHeading","label":"Declarations"}}]}}