Maartje M. van de Meeberg, Janani Sundaresan, Marry Lin, Gerrit Jansen, Eduard A. Struys, Herma H. Fidder, Bas Oldenburg, Wout G. N. Mares, Nofel Mahmmod, Dirk P. van Asseldonk, Svend T. Rietdijk, Loes H. C. Nissen, Nanne K. H. de Boer, Gerd Bouma, Maja Bulatović Ćalasan, Robert de Jonge, On behalf on the Dutch Initiative on Crohn and Colitis (ICC)
{"title":"克罗恩病患者的目标肠粘膜和白细胞中的甲氨蝶呤蓄积与非目标红细胞中的甲氨蝶呤蓄积不同。","authors":"Maartje M. van de Meeberg, Janani Sundaresan, Marry Lin, Gerrit Jansen, Eduard A. Struys, Herma H. Fidder, Bas Oldenburg, Wout G. N. Mares, Nofel Mahmmod, Dirk P. van Asseldonk, Svend T. Rietdijk, Loes H. C. Nissen, Nanne K. H. de Boer, Gerd Bouma, Maja Bulatović Ćalasan, Robert de Jonge, On behalf on the Dutch Initiative on Crohn and Colitis (ICC)","doi":"10.1111/bcpt.14047","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG<sub>3</sub> concentrations correlate with efficacy in patients with Crohn's disease (CD). Since RBCs are not involved in pathogenesis of CD and lack extended MTX metabolism, we determined MTX-PGs accumulation in peripheral blood mononuclear cells (PBMCs: effector cells) and intestinal mucosa (target cells) and compared those with RBCs as a potential more precise biomarker.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>In a multicentre prospective cohort study, blood samples of patients with CD were collected during the first year of MTX therapy. Mucosal biopsies were obtained from non-inflamed rectum and/or inflamed intestine. MTX-PGs concentrations in mucosa, PBMCs and RBCs were measured by liquid chromatography–tandem mass spectrometry.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>From 80 patients with CD, a total of 27 mucosal biopsies, 9 PBMC and 212 RBC samples were collected. From 12 weeks of MTX therapy onwards, MTX-PG<sub>3</sub> was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG<sub>1</sub> (48%), which accounted for an 18 times higher concentration than in RBCs. Long-chain MTX-PGs were highly present in mucosa: 21% of MTX-PG<sub>total</sub> was MTX-PG<sub>5</sub>. MTX-PG<sub>6</sub> was measurable in all biopsies.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD.</p>\n </section>\n </div>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"135 3","pages":"308-320"},"PeriodicalIF":2.7000,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.14047","citationCount":"0","resultStr":"{\"title\":\"Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease\",\"authors\":\"Maartje M. van de Meeberg, Janani Sundaresan, Marry Lin, Gerrit Jansen, Eduard A. Struys, Herma H. Fidder, Bas Oldenburg, Wout G. N. Mares, Nofel Mahmmod, Dirk P. van Asseldonk, Svend T. Rietdijk, Loes H. C. Nissen, Nanne K. H. de Boer, Gerd Bouma, Maja Bulatović Ćalasan, Robert de Jonge, On behalf on the Dutch Initiative on Crohn and Colitis (ICC)\",\"doi\":\"10.1111/bcpt.14047\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG<sub>3</sub> concentrations correlate with efficacy in patients with Crohn's disease (CD). Since RBCs are not involved in pathogenesis of CD and lack extended MTX metabolism, we determined MTX-PGs accumulation in peripheral blood mononuclear cells (PBMCs: effector cells) and intestinal mucosa (target cells) and compared those with RBCs as a potential more precise biomarker.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>In a multicentre prospective cohort study, blood samples of patients with CD were collected during the first year of MTX therapy. Mucosal biopsies were obtained from non-inflamed rectum and/or inflamed intestine. MTX-PGs concentrations in mucosa, PBMCs and RBCs were measured by liquid chromatography–tandem mass spectrometry.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>From 80 patients with CD, a total of 27 mucosal biopsies, 9 PBMC and 212 RBC samples were collected. From 12 weeks of MTX therapy onwards, MTX-PG<sub>3</sub> was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG<sub>1</sub> (48%), which accounted for an 18 times higher concentration than in RBCs. Long-chain MTX-PGs were highly present in mucosa: 21% of MTX-PG<sub>total</sub> was MTX-PG<sub>5</sub>. MTX-PG<sub>6</sub> was measurable in all biopsies.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD.</p>\\n </section>\\n </div>\",\"PeriodicalId\":8733,\"journal\":{\"name\":\"Basic & Clinical Pharmacology & Toxicology\",\"volume\":\"135 3\",\"pages\":\"308-320\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2024-07-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.14047\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Basic & Clinical Pharmacology & Toxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/bcpt.14047\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Basic & Clinical Pharmacology & Toxicology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/bcpt.14047","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease
Background
Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG3 concentrations correlate with efficacy in patients with Crohn's disease (CD). Since RBCs are not involved in pathogenesis of CD and lack extended MTX metabolism, we determined MTX-PGs accumulation in peripheral blood mononuclear cells (PBMCs: effector cells) and intestinal mucosa (target cells) and compared those with RBCs as a potential more precise biomarker.
Methods
In a multicentre prospective cohort study, blood samples of patients with CD were collected during the first year of MTX therapy. Mucosal biopsies were obtained from non-inflamed rectum and/or inflamed intestine. MTX-PGs concentrations in mucosa, PBMCs and RBCs were measured by liquid chromatography–tandem mass spectrometry.
Results
From 80 patients with CD, a total of 27 mucosal biopsies, 9 PBMC and 212 RBC samples were collected. From 12 weeks of MTX therapy onwards, MTX-PG3 was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG1 (48%), which accounted for an 18 times higher concentration than in RBCs. Long-chain MTX-PGs were highly present in mucosa: 21% of MTX-PGtotal was MTX-PG5. MTX-PG6 was measurable in all biopsies.
Conclusions
MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD.
期刊介绍：
Basic & Clinical Pharmacology and Toxicology is an independent journal, publishing original scientific research in all fields of toxicology, basic and clinical pharmacology. This includes experimental animal pharmacology and toxicology and molecular (-genetic), biochemical and cellular pharmacology and toxicology. It also includes all aspects of clinical pharmacology: pharmacokinetics, pharmacodynamics, therapeutic drug monitoring, drug/drug interactions, pharmacogenetics/-genomics, pharmacoepidemiology, pharmacovigilance, pharmacoeconomics, randomized controlled clinical trials and rational pharmacotherapy. For all compounds used in the studies, the chemical constitution and composition should be known, also for natural compounds.
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