Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis

Katsunori Suzuki, Kazuyoshi Saito, Shizuyo Tsujimura, Shingo Nakayamada, Kunihiro Yamaoka, Norifumi Sawamukai, Shigeru Iwata, Masao Nawata, Kazuhisa Nakano, Yoshiya Tanaka

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Objective. Tacrolimus, a calcineurin inhibitor, is used for treatment of rheumatoid arthritis (RA). It also inhibits functions of P-glycoprotein, which is involved in drug resistance. We examined the mechanisms of early response to 2-week tacrolimus treatment in patients with RA. Methods. One hundred thirteen patients with refractory RA despite at least 3 antirheumatic agents, including methotrexate, were treated with tacrolimus (1.5-3 mg/day) and the response was assessed at 2 weeks. Expression of the multidrug resistance (MDR-1) gene and P-glycoprotein was assessed in peripheral blood mononuclear cells (PBMC) collected from 113 patients and 40 healthy subjects. The drug exclusion function by the P-glycoprotein was measured by the residual amount of intracellular tritium-labeled dexamethasone cell/medium ratio (C/M ratio). Results. The disease activity of enrolled patients was 5.8 ±1.2 (mean ± SD) by DAS28 erythrocyte sedimentation rate. A good response to tacrolimus was noted at 2 weeks in 22 of 113 patients. At baseline, PBMC of patients with RA showed upregulated expression of MDR-1 gene and P-glycoprotein and low C/Mratio. The response to tacrolimus correlated with P-glycoprotein expression and C/M ratio. A significant improvement in C/M ratio was noted after 2 weeks of treatment. The C/M ratio correlated significantly with P-glycoprotein expression on CD4+ lymphocytes. Conclusion. Early efficacy of tacrolimus treatment depended on its inhibitory effect on the drug exclusion function of P-glycoprotein, leading to restoration of intracellular therapeutic levels of corticosteroids and clinical improvement. Evaluation of P-glycoprotein expression on lymphocytes is potentially useful for predicting the response to RA treatment. The Journal of Rheumatology

Original languageEnglish
Pages (from-to)512-520
Number of pages9
JournalJournal of Rheumatology
Volume37
Issue number3
DOIs
Publication statusPublished - 2010 Mar
Externally publishedYes

Fingerprint

P-Glycoprotein
Tacrolimus
Rheumatoid Arthritis
Lymphocytes
MDR Genes
Therapeutics
Blood Cells
Antirheumatic Agents
Tritium
Blood Sedimentation
Rheumatology
Multiple Drug Resistance
Calcineurin Inhibitors
Drug Resistance
Methotrexate
Pharmaceutical Preparations
Dexamethasone
Healthy Volunteers
Adrenal Cortex Hormones

Keywords

  • Calcineurin inhibitor
  • Drug resistance
  • P-glycoprotein
  • Rheumatoid arthritis
  • Tacrolimus

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy

Cite this

Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis. / Suzuki, Katsunori; Saito, Kazuyoshi; Tsujimura, Shizuyo; Nakayamada, Shingo; Yamaoka, Kunihiro; Sawamukai, Norifumi; Iwata, Shigeru; Nawata, Masao; Nakano, Kazuhisa; Tanaka, Yoshiya.

In: Journal of Rheumatology, Vol. 37, No. 3, 03.2010, p. 512-520.

Research output: Contribution to journalArticle

Suzuki, K, Saito, K, Tsujimura, S, Nakayamada, S, Yamaoka, K, Sawamukai, N, Iwata, S, Nawata, M, Nakano, K & Tanaka, Y 2010, 'Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis', Journal of Rheumatology, vol. 37, no. 3, pp. 512-520. https://doi.org/10.3899/jrheum.090048
Suzuki, Katsunori ; Saito, Kazuyoshi ; Tsujimura, Shizuyo ; Nakayamada, Shingo ; Yamaoka, Kunihiro ; Sawamukai, Norifumi ; Iwata, Shigeru ; Nawata, Masao ; Nakano, Kazuhisa ; Tanaka, Yoshiya. / Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis. In: Journal of Rheumatology. 2010 ; Vol. 37, No. 3. pp. 512-520.
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abstract = "Objective. Tacrolimus, a calcineurin inhibitor, is used for treatment of rheumatoid arthritis (RA). It also inhibits functions of P-glycoprotein, which is involved in drug resistance. We examined the mechanisms of early response to 2-week tacrolimus treatment in patients with RA. Methods. One hundred thirteen patients with refractory RA despite at least 3 antirheumatic agents, including methotrexate, were treated with tacrolimus (1.5-3 mg/day) and the response was assessed at 2 weeks. Expression of the multidrug resistance (MDR-1) gene and P-glycoprotein was assessed in peripheral blood mononuclear cells (PBMC) collected from 113 patients and 40 healthy subjects. The drug exclusion function by the P-glycoprotein was measured by the residual amount of intracellular tritium-labeled dexamethasone cell/medium ratio (C/M ratio). Results. The disease activity of enrolled patients was 5.8 ±1.2 (mean ± SD) by DAS28 erythrocyte sedimentation rate. A good response to tacrolimus was noted at 2 weeks in 22 of 113 patients. At baseline, PBMC of patients with RA showed upregulated expression of MDR-1 gene and P-glycoprotein and low C/Mratio. The response to tacrolimus correlated with P-glycoprotein expression and C/M ratio. A significant improvement in C/M ratio was noted after 2 weeks of treatment. The C/M ratio correlated significantly with P-glycoprotein expression on CD4+ lymphocytes. Conclusion. Early efficacy of tacrolimus treatment depended on its inhibitory effect on the drug exclusion function of P-glycoprotein, leading to restoration of intracellular therapeutic levels of corticosteroids and clinical improvement. Evaluation of P-glycoprotein expression on lymphocytes is potentially useful for predicting the response to RA treatment. The Journal of Rheumatology",
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AU - Nakayamada, Shingo

AU - Yamaoka, Kunihiro

AU - Sawamukai, Norifumi

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