{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:18:02Z","timestamp":1789564682948,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Methotrexate (MTX) is a cornerstone drug used to treat immune-mediated inflammatory diseases (IMIDs) in low doses (10\u201330 mg\/week), and malignancies in high doses (5000 mg\/m2\/2 weeks). Its active metabolites, Methotrexate polyglutamates (MTX-PG2\u20135), quantified in erythrocytes, are associated with efficacy. This study aimed to compare erythrocyte MTX-PG concentrations in patients with IMIDs and pediatric acute lymphoblastic leukemia (ped-ALL) treated with low-dose or high-dose MTX, respectively, and to identify clinical, demographic, and treatment-related factors influencing their concentration. Methods: A total of 567 patients with rheumatoid arthritis, juvenile idiopathic arthritis, Crohn\u2019s disease, sarcoidosis, and ped-ALL were included. Erythrocyte MTX-PG concentration data was collected after 3 months (2.5 months for ped-ALL patients) of MTX-use. Multivariate linear regressing modelling adjusting for age, sex, body mass index (BMI), smoking status, starting MTX dose, route of MTX administration, use of predniso(lo)ne, disease-modifying anti-rheumatic drugs (DMARDs), and folic (or folinic) acid was performed. Results: Intravenous high-dose MTX increased MTX-PG4&amp;5 accumulation. Despite 50-fold higher doses in ped-ALL, MTX-PG2\u20135sum concentrations were similar to those seen with subcutaneous low-dose MTX used in IMIDs. Age positively influenced MTX-PG concentrations, while DMARD use reduced MTX-PG2\u20133&amp;5 concentrations. Interestingly, predniso(lo)ne use was associated with higher MTX-PG4&amp;5 concentrations and folic (or folinic) acid with higher MTX-PG3\u20135 concentrations. Conclusions: This is the first study to compare erythrocyte MTX-PG concentration in low-dose and high-dose patients. Intravenous high-dose MTX administration increased long-chain MTX-PG4&amp;5 concentrations, with MTX-PG2\u20135sum concentrations similar compared to low-dose subcutaneous MTX use. This study demonstrated that route of administration, age, and concomitant therapies such as DMARDs, predniso(lo)ne, and folic (or folinic) acid significantly influence MTX-PG concentrations.<\/jats:p>","DOI":"10.3390\/ph19020267","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T12:51:56Z","timestamp":1770209516000},"page":"267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Drivers of Methotrexate Polyglutamate Concentration in Erythrocytes: Insights from Immune-Mediated Inflammatory Diseases and Pediatric Acute Lymphoblastic Leukemia"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7905-0214","authenticated-orcid":false,"given":"Janani","family":"Sundaresan","sequence":"first","affiliation":[{"name":"Laboratory of Specialized Diagnostics & Research, Department of Laboratory Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wout J.","family":"Hamelink","sequence":"additional","affiliation":[{"name":"Laboratory of Specialized Diagnostics & Research, Department of Laboratory Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6725-6719","authenticated-orcid":false,"given":"Renske C. F.","family":"Hebing","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Sint Maartenskliniek, 6574 NA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maartje","family":"van de Meeberg","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Gastroenterology and Hepatology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montse","family":"Janssen Bon\u00e1s","sequence":"additional","affiliation":[{"name":"ILD Center of Excellence (Member of the European Reference Network-Lung), St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5822-7668","authenticated-orcid":false,"given":"Inge M.","family":"van der Sluis","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6628-6222","authenticated-orcid":false,"given":"Pascal H. P.","family":"de Jong","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn","family":"Heymans","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Data Science, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3454-0094","authenticated-orcid":false,"given":"Robert","family":"de Jonge","sequence":"additional","affiliation":[{"name":"Laboratory of Specialized Diagnostics & Research, Department of Laboratory Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9213-107X","authenticated-orcid":false,"given":"Maurits C. F. J.","family":"de Rotte","sequence":"additional","affiliation":[{"name":"Laboratory of Specialized Diagnostics & Research, Department of Laboratory Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Bulatovi\u0107-\u0106alasan","sequence":"additional","affiliation":[{"name":"Laboratory of Specialized Diagnostics & Research, Department of Laboratory Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/0065-2571(94)90025-6","article-title":"The Methotrexate Story: A Paradigm For Development Of Cancer Chemotherapeutic Agents","volume":"34","author":"Huennekens","year":"1994","journal-title":"Adv. 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