Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease

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

doi:10.1111/bcpt.14047

Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease

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,

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG 3 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-PG 3 was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG 1 (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 total was MTX-PG 5. MTX-PG 6 was measurable in all biopsies.

CONCLUSIONS: MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD.

Original language	English
Pages (from-to)	308-320
Number of pages	13
Journal	Basic & Clinical Pharmacology & Toxicology
Volume	135
Issue number	3
Early online date	8 Jul 2024
DOIs	https://doi.org/10.1111/bcpt.14047
Publication status	Published - Sept 2024

Keywords

Crohn's disease
methotrexate
pharmacokinetics
therapeutic drug monitoring

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Basic Clin Pharma Tox - 2024 - Meeberg - Methotrexate accumulation in target intestinal mucosa and white blood cellsFinal published version, 942 KBLicence: CC BY-NC-ND

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van de Meeberg, M. M., Sundaresan, J., Lin, M., Jansen, G., Struys, E. A., Fidder, H. H., Oldenburg, B., Mares, W. G. N., Mahmmod, N., van Asseldonk, D. P., Rietdijk, S. T., Nissen, L. H. C., de Boer, N. K. H., Bouma, G., Ćalasan, M. B., de Jonge, R. (2024). Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease. Basic & Clinical Pharmacology & Toxicology, 135(3), 308-320. https://doi.org/10.1111/bcpt.14047

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title = "Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease",

abstract = "BACKGROUND: Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG 3 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-PG 3 was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG 1 (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 total was MTX-PG 5. MTX-PG 6 was measurable in all biopsies. CONCLUSIONS: MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD.",

keywords = "Crohn's disease, methotrexate, pharmacokinetics, therapeutic drug monitoring",

author = "{van de Meeberg}, {Maartje M} and Janani Sundaresan and Marry Lin and Gerrit Jansen and Struys, {Eduard A} and Fidder, {Herma H} and Bas Oldenburg and Mares, {Wout G N} and Nofel Mahmmod and {van Asseldonk}, {Dirk P} and Rietdijk, {Svend T} and Nissen, {Loes H C} and {de Boer}, {Nanne K H} and Gerd Bouma and {\'C}alasan, {Maja Bulatovi{\'c}} and {de Jonge}, Robert",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).",

year = "2024",

month = sep,

doi = "10.1111/bcpt.14047",

language = "English",

volume = "135",

pages = "308--320",

journal = "Basic & Clinical Pharmacology & Toxicology",

issn = "1742-7835",

publisher = "Wiley-Blackwell",

number = "3",

}

van de Meeberg, MM, Sundaresan, J, Lin, M, Jansen, G, Struys, EA, Fidder, HH , Oldenburg, B, Mares, WGN, Mahmmod, N, van Asseldonk, DP, Rietdijk, ST, Nissen, LHC, de Boer, NKH, Bouma, G, Ćalasan, MB, de Jonge, R 2024, 'Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease', Basic & Clinical Pharmacology & Toxicology, vol. 135, no. 3, pp. 308-320. https://doi.org/10.1111/bcpt.14047

Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease. / van de Meeberg, Maartje M; Sundaresan, Janani; Lin, Marry et al.
In: Basic & Clinical Pharmacology & Toxicology, Vol. 135, No. 3, 09.2024, p. 308-320.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease

AU - van de Meeberg, Maartje M

AU - Sundaresan, Janani

AU - Lin, Marry

AU - Jansen, Gerrit

AU - Struys, Eduard A

AU - Fidder, Herma H

AU - Oldenburg, Bas

AU - Mares, Wout G N

AU - Mahmmod, Nofel

AU - van Asseldonk, Dirk P

AU - Rietdijk, Svend T

AU - Nissen, Loes H C

AU - de Boer, Nanne K H

AU - Bouma, Gerd

AU - Ćalasan, Maja Bulatović

AU - de Jonge, Robert

N1 - Publisher Copyright: © 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

PY - 2024/9

Y1 - 2024/9

N2 - BACKGROUND: Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG 3 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-PG 3 was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG 1 (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 total was MTX-PG 5. MTX-PG 6 was measurable in all biopsies. CONCLUSIONS: MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD.

AB - BACKGROUND: Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG 3 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-PG 3 was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG 1 (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 total was MTX-PG 5. MTX-PG 6 was measurable in all biopsies. CONCLUSIONS: MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD.

KW - Crohn's disease

KW - methotrexate

KW - pharmacokinetics

KW - therapeutic drug monitoring

UR - http://www.scopus.com/inward/record.url?scp=85197791690&partnerID=8YFLogxK

U2 - 10.1111/bcpt.14047

DO - 10.1111/bcpt.14047

M3 - Article

C2 - 38973551

SN - 1742-7835

VL - 135

SP - 308

EP - 320

JO - Basic & Clinical Pharmacology & Toxicology

JF - Basic & Clinical Pharmacology & Toxicology

IS - 3

ER -

Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease

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