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Etanercept overcomes P-glycoprotein-induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis

  • Original Article
  • Published:
Modern Rheumatology

Abstract

P-glycoprotein (P-gp) on activated lymphocytes is an adenosine triphosphate (ATP)-binding cassette transporter that causes drug resistance by exclusion of intracellular drugs in patients with active rheumatoid arthritis (RA). However, infliximab with methotrexate (MTX) can overcome P-gp-mediated drug resistance. We encounter patients who cannot continue infliximab or MTX. Here we tested how etanercept affected P-gp-mediated drug resistance in such intractable RA patients. Peripheral lymphocytes of 11 RA patients (3 switched from infliximab and 8 who could not be treated with MTX) were analyzed for P-gp expression by flow cytometry and for drug exclusion using radioisotope-labeled dexamethasone. Activated lymphocytes of RA patients overexpressed P-gp and coexpressed CD69. Incubation of these lymphocytes with dexamethasone in vitro reduced intracellular dexamethasone levels. Two-week etanercept therapy significantly reduced P-gp expression and eliminated such P-gp- and CD69-high-expressing subgroup. The reduction in P-gp resulted in recovery of intracellular dexamethasone levels in lymphocytes and improvement of disease activity, thus allowing tapering of corticosteroids. None of the patients experienced any severe adverse effects. Etanercept is useful for overcoming P-gp-mediated treatment resistance in intractable RA patients who have to discontinue infliximab or are intolerant to MTX.

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Acknowledgments

The authors thank Ms. T. Adachi for excellent technical assistance. This work was supported in part by Research Grants-In-Aid for Scientific Research from the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science, and Technology of Japan and University of Occupational and Environmental Health, Japan.

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Authors and Affiliations

  1. The First Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu, 807-8555, Japan

    Shizuyo Tsujimura, Kazuyoshi Saito, Shingo Nakayamada & Yoshiya Tanaka

Authors
  1. Shizuyo Tsujimura
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  2. Kazuyoshi Saito
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  3. Shingo Nakayamada
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  4. Yoshiya Tanaka
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Correspondence to Yoshiya Tanaka.

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Tsujimura, S., Saito, K., Nakayamada, S. et al. Etanercept overcomes P-glycoprotein-induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis. Mod Rheumatol 20, 139–146 (2010). https://doi.org/10.1007/s10165-009-0247-0

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  • DOI: https://doi.org/10.1007/s10165-009-0247-0

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