{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T23:26:24Z","timestamp":1793834784021,"version":"4.6.1"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"22","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"name":"National Science and Technology Council, Taiwan","award":["NSTC 112-2320-B-002-029-MY3"],"award-info":[{"award-number":["NSTC 112-2320-B-002-029-MY3"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Anal Bioanal Chem"],"published-print":{"date-parts":[[2026,11]]},"DOI":"10.1007\/s00216-026-06728-3","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:53:28Z","timestamp":1787043208000},"page":"7339-7352","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development and validation of an LC\u2013MS\/MS method for the comprehensive quantification of tamoxifen and its metabolites in volumetric absorptive microsampling: clinical application in breast cancer patients"],"prefix":"10.1007","volume":"418","author":[{"given":"Ya-Chu","family":"Kuo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsuan-Yu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsuan-Hui","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Jiuan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Hua","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"issue":"5","key":"6728_CR1","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1200\/jco.18.01160","volume":"37","author":"HJ Burstein","year":"2019","unstructured":"Burstein HJ, Lacchetti C, Anderson H, Buchholz TA, Davidson NE, Gelmon KA, et al. Adjuvant endocrine therapy for women with hormone receptor\u2013positive breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol. 2019;37(5):423\u201338. https:\/\/doi.org\/10.1200\/jco.18.01160.","journal-title":"J Clin Oncol"},{"issue":"1","key":"6728_CR2","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-017-0916-4","volume":"19","author":"T Helland","year":"2017","unstructured":"Helland T, Henne N, Bifulco E, Naume B, Borgen E, Kristensen VN, et al. Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients. Breast Cancer Res. 2017;19(1):125. https:\/\/doi.org\/10.1186\/s13058-017-0916-4.","journal-title":"Breast Cancer Res"},{"issue":"4","key":"6728_CR3","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1002\/1878-0261.12865","volume":"15","author":"T Helland","year":"2021","unstructured":"Helland T, Naume B, Hustad S, Bifulco E, Kvaloy JT, S\u00e6tersdal AB, et al. Low Z-4OHtam concentrations are associated with adverse clinical outcome among early stage premenopausal breast cancer patients treated with adjuvant tamoxifen. Mol Oncol. 2021;15(4):957\u201367. https:\/\/doi.org\/10.1002\/1878-0261.12865.","journal-title":"Mol Oncol"},{"issue":"3","key":"6728_CR4","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1007\/s10549-016-4083-6","volume":"161","author":"A Schultink","year":"2017","unstructured":"Schultink A, Alexi X, van Werkhoven E, Madlensky L, Natarajan L, Flatt SW, et al. An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome. Breast Cancer Res Treat. 2017;161(3):567\u201374. https:\/\/doi.org\/10.1007\/s10549-016-4083-6.","journal-title":"Breast Cancer Res Treat"},{"issue":"11","key":"6728_CR5","doi-asserted-by":"publisher","first-page":"1897","DOI":"10.1093\/carcin\/23.11.1897(accessed10\/2\/2025)","volume":"23","author":"DJ Boocock","year":"2002","unstructured":"Boocock DJ, Brown K, Gibbs AH, Sanchez E, Turteltaub KW, White INH. Identification of human CYP forms involved in the activation of tamoxifen and irreversible binding to DNA. Carcinogenesis. 2002;23(11):1897\u2013902. https:\/\/doi.org\/10.1093\/carcin\/23.11.1897(accessed10\/2\/2025).","journal-title":"Carcinogenesis"},{"issue":"8","key":"6728_CR6","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1124\/dmd.30.8.869","volume":"30","author":"HK Crewe","year":"2002","unstructured":"Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam EMJ. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4\u2032-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002;30(8):869\u201374. https:\/\/doi.org\/10.1124\/dmd.30.8.869.","journal-title":"Drug Metab Dispos"},{"issue":"1","key":"6728_CR7","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1046\/j.1365-2125.2003.01970.x","volume":"57","author":"JK Coller","year":"2004","unstructured":"Coller JK, Krebsfaenger N, Klein K, Wolbold R, N\u00fcssler A, Neuhaus P, et al. Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity. Br J Clin Pharmacol. 2004;57(1):105\u201311. https:\/\/doi.org\/10.1046\/j.1365-2125.2003.01970.x.","journal-title":"Br J Clin Pharmacol"},{"issue":"3","key":"6728_CR8","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1124\/jpet.104.065607","volume":"310","author":"Z Desta","year":"2004","unstructured":"Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004;310(3):1062\u201375. https:\/\/doi.org\/10.1124\/jpet.104.065607.","journal-title":"J Pharmacol Exp Ther"},{"issue":"10","key":"6728_CR9","doi-asserted-by":"publisher","first-page":"1770","DOI":"10.1373\/clinchem.2008.121756","volume":"55","author":"H Brauch","year":"2009","unstructured":"Brauch H, M\u00fcrdter TE, Eichelbaum M, Schwab M. Pharmacogenomics of tamoxifen therapy. Clin Chem. 2009;55(10):1770\u201382. https:\/\/doi.org\/10.1373\/clinchem.2008.121756.","journal-title":"Clin Chem"},{"issue":"2","key":"6728_CR10","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1046\/j.1365-2125.2002.01614.x","volume":"54","author":"JK Coller","year":"2002","unstructured":"Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, et al. The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol. 2002;54(2):157\u201367. https:\/\/doi.org\/10.1046\/j.1365-2125.2002.01614.x.","journal-title":"Br J Clin Pharmacol"},{"issue":"5","key":"6728_CR11","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1007\/s00280-004-0926-7","volume":"55","author":"YC Lim","year":"2005","unstructured":"Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol. 2005;55(5):471\u20138. https:\/\/doi.org\/10.1007\/s00280-004-0926-7.","journal-title":"Cancer Chemother Pharmacol"},{"issue":"2","key":"6728_CR12","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1023\/B:BREA.0000025406.31193.e8","volume":"85","author":"MD Johnson","year":"2004","unstructured":"Johnson MD, Zuo H, Lee K-H, Trebley JP, Rae JM, Weatherman RV, et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004;85(2):151\u20139. https:\/\/doi.org\/10.1023\/B:BREA.0000025406.31193.e8.","journal-title":"Breast Cancer Res Treat"},{"issue":"10","key":"6728_CR13","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1124\/dmd.104.000802","volume":"33","author":"P Parte","year":"2005","unstructured":"Parte P, Kupfer D. Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. Drug Metab Dispos. 2005;33(10):1446\u201352. https:\/\/doi.org\/10.1124\/dmd.104.000802.","journal-title":"Drug Metab Dispos"},{"issue":"1-2","key":"6728_CR14","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1080\/03602530600569919","volume":"38","author":"SK Krueger","year":"2006","unstructured":"Krueger SK, VanDyke JE, Williams DE, Hines RN. The role of flavin-containing monooxygenase (FMO) in the metabolism of tamoxifen and other tertiary amines. Drug Metab Rev. 2006;38(1\u20132):139\u201347. https:\/\/doi.org\/10.1080\/03602530600569919.","journal-title":"Drug Metab Rev"},{"issue":"24","key":"6728_CR15","doi-asserted-by":"publisher","first-page":"10186","DOI":"10.1021\/ac102337d","volume":"82","author":"M Jaremko","year":"2010","unstructured":"Jaremko M, Kasai Y, Barginear MF, Raptis G, Desnick RJ, Yu C. Tamoxifen metabolite isomer separation and quantification by liquid chromatography\u2212tandem mass spectrometry. Anal Chem. 2010;82(24):10186\u201393. https:\/\/doi.org\/10.1021\/ac102337d.","journal-title":"Anal Chem"},{"issue":"1","key":"6728_CR16","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/s10549-014-2999-2","volume":"146","author":"NG Jager","year":"2014","unstructured":"Jager NG, Rosing H, Schellens JH, Beijnen JH, Linn SC. Use of dried blood spots for the determination of serum concentrations of tamoxifen and endoxifen. Breast Cancer Res Treat. 2014;146(1):137\u201344. https:\/\/doi.org\/10.1007\/s10549-014-2999-2.","journal-title":"Breast Cancer Res Treat"},{"key":"6728_CR17","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/j.talanta.2014.10.040","volume":"132","author":"MV Antunes","year":"2015","unstructured":"Antunes MV, Raymundo S, de Oliveira V, Staudt DE, G\u00f6ssling G, Peteffi GP, et al. Ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots\u2014development, validation and clinical application during breast cancer adjuvant therapy. Talanta. 2015;132:775\u201384. https:\/\/doi.org\/10.1016\/j.talanta.2014.10.040.","journal-title":"Talanta"},{"key":"6728_CR18","doi-asserted-by":"publisher","unstructured":"Maggadani BP, Harahap Y, Haryono SJ, Untu CW. Analysis of tamoxifen and its metabolites in dried blood spot and volumetric absorptive microsampling: comparison and clinical application. Heliyon. 2021;7(6):e07275. https:\/\/doi.org\/10.1016\/j.heliyon.2021.e07275","DOI":"10.1016\/j.heliyon.2021.e07275"},{"key":"6728_CR19","doi-asserted-by":"publisher","unstructured":"Maggadani BP, Harmita, Haryono SJ, Rinaldi MR, Harahap Y. Volumetric absorptive microsampling as a new biosampling tool for monitoring of tamoxifen, endoxifen, 4-OH tamoxifen and N-desmethyltamoxifen in breast cancer patients. Drug Des Dev Ther. 2021;15:2417\u20132430. https:\/\/doi.org\/10.2147\/dddt.S286409.","DOI":"10.2147\/dddt.S286409"},{"issue":"5-6","key":"6728_CR20","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1002\/ansa.202300011","volume":"4","author":"MU Thangavelu","year":"2023","unstructured":"Thangavelu MU, Wouters B, Kindt A, Reiss IKM, Hankemeier T. Blood microsampling technologies: innovations and applications in 2022. Anal Sci Adv. 2023;4(5\u20136):154\u201380. https:\/\/doi.org\/10.1002\/ansa.202300011.","journal-title":"Anal Sci Adv"},{"issue":"15","key":"6728_CR21","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1080\/17576180.2025.2546782","volume":"17","author":"M Protti","year":"2025","unstructured":"Protti M, Mandrioli R, Santos HM, Lodeiro C, Capelo-Mart\u00ednez JL, Mercolini L. How microsampling is impacting pharmacokinetic and toxicokinetic studies: volumetric absorptive microsampling (VAMS). Bioanalysis. 2025;17(15):997\u20131009. https:\/\/doi.org\/10.1080\/17576180.2025.2546782.","journal-title":"Bioanalysis"},{"key":"6728_CR22","unstructured":"U.S. Food and Drug Administration. Bioanalytical method validation and study sample analysis, Guidance for Industry; 2022."},{"issue":"3","key":"6728_CR23","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1007\/s10549-013-2826-1","volume":"143","author":"NG Jager","year":"2014","unstructured":"Jager NG, Rosing H, Schellens JH, Linn SC, Beijnen JH. Tamoxifen dose and serum concentrations of tamoxifen and six of its metabolites in routine clinical outpatient care. Breast Cancer Res Treat. 2014;143(3):477\u201383. https:\/\/doi.org\/10.1007\/s10549-013-2826-1.","journal-title":"Breast Cancer Res Treat"},{"issue":"5","key":"6728_CR24","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1038\/clpt.2011.32","volume":"89","author":"L Madlensky","year":"2011","unstructured":"Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011;89(5):718\u201325. https:\/\/doi.org\/10.1038\/clpt.2011.32.","journal-title":"Clin Pharmacol Ther"},{"issue":"4","key":"6728_CR25","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1038\/clpt.2011.153","volume":"90","author":"MF Barginear","year":"2011","unstructured":"Barginear MF, Jaremko M, Peter I, Yu C, Kasai Y, Kemeny M, et al. Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: effect on active metabolite isomers and the antiestrogenic activity score. Clin Pharmacol Ther. 2011;90(4):605\u201311. https:\/\/doi.org\/10.1038\/clpt.2011.153.","journal-title":"Clin Pharmacol Ther"},{"issue":"3","key":"6728_CR26","doi-asserted-by":"publisher","first-page":"2511","DOI":"10.1021\/acs.analchem.9b04063","volume":"92","author":"R-S Jhang","year":"2020","unstructured":"Jhang R-S, Lin S-Y, Peng Y-F, Chao H-C, Tsai IL, Lin Y-T, et al. Using the PCI-IS method to simultaneously estimate blood volume and quantify nonvitamin K antagonist oral anticoagulant concentrations in dried blood spots. Anal Chem. 2020;92(3):2511\u20138. https:\/\/doi.org\/10.1021\/acs.analchem.9b04063.","journal-title":"Anal Chem"},{"key":"6728_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.aca.2022.340650","volume":"1239","author":"C-N Cheng","year":"2023","unstructured":"Cheng C-N, Peng Y-F, Chen J-Y, Chen G-Y, Weng T-I, Kuo C-H. Development of the dried blood spot preparation protocol for comprehensive evaluation of the hematocrit effect. Anal Chim Acta. 2023;1239:340650. https:\/\/doi.org\/10.1016\/j.aca.2022.340650.","journal-title":"Anal Chim Acta"},{"key":"6728_CR28","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.talanta.2019.01.014","volume":"197","author":"MGM Kok","year":"2019","unstructured":"Kok MGM, Nix C, Nys G, Fillet M. Targeted metabolomics of whole blood using volumetric absorptive microsampling. Talanta. 2019;197:49\u201358. https:\/\/doi.org\/10.1016\/j.talanta.2019.01.014.","journal-title":"Talanta"},{"issue":"4","key":"6728_CR29","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1097\/ftd.0000000000001083","volume":"45","author":"P Dodeja","year":"2023","unstructured":"Dodeja P, Giannoutsos S, Caritis S, Venkataramanan R. Applications of volumetric absorptive microsampling technique: a systematic critical review. Ther Drug Monit. 2023;45(4):431\u201362. https:\/\/doi.org\/10.1097\/ftd.0000000000001083.","journal-title":"Ther Drug Monit"},{"issue":"21","key":"6728_CR30","doi-asserted-by":"publisher","first-page":"2789","DOI":"10.4155\/bio.15.181","volume":"7","author":"V Houbart","year":"2015","unstructured":"Houbart V, Cobraiville G, Servais AC, Napp A, Merville MP, Fillet M. Hepcidin determination in dried blood by microfluidic LC-MS\/MS: comparison of DBS and volumetric absorptive microsampling for matrix effect and recovery. Bioanalysis. 2015;7(21):2789\u201399. https:\/\/doi.org\/10.4155\/bio.15.181.","journal-title":"Bioanalysis"},{"issue":"3","key":"6728_CR31","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.4781","volume":"34","author":"S Mohamed","year":"2020","unstructured":"Mohamed S, Riva R, Moresco M, Plazzi G, Contin M. Development and validation of volumetric absorptive microsampling coupled with UHPLC\u2013MS\/MS for the analysis of gamma-hydroxybutyric acid in human blood. Biomed Chromatogr. 2020;34(3):e4781. https:\/\/doi.org\/10.1002\/bmc.4781.","journal-title":"Biomed Chromatogr"}],"container-title":["Analytical and Bioanalytical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00216-026-06728-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00216-026-06728-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00216-026-06728-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T23:07:40Z","timestamp":1793833660000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00216-026-06728-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":31,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["6728"],"URL":"https:\/\/doi.org\/10.1007\/s00216-026-06728-3","relation":{},"ISSN":["1618-2642","1618-2650"],"issn-type":[{"value":"1618-2642","type":"print"},{"value":"1618-2650","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]},"assertion":[{"value":"21 May 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Breast cancer patients were recruited from National Taiwan University Hospital (NTUH), and the study was approved by the Research Ethics Committee of NTUH (202301089RINA). Blank whole blood and plasma samples were obtained from healthy volunteers, and the collection of blood samples was approved by the Research Ethics Committee of NTUH (202603064RINB). Written informed consent was obtained from all patients and healthy volunteers.","order":1,"name":"Ethics","label":"Ethics approval and source of biological material","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}