Document Detail


Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis.
MedLine Citation:
PMID:  20080907     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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/M ratio. 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.
Authors:
Katsunori Suzuki; Kazuyoshi Saito; Shizuyo Tsujimura; Shingo Nakayamada; Kunihiro Yamaoka; Norifumi Sawamukai; Shigeru Iwata; Masao Nawata; Kazuhisa Nakano; Yoshiya Tanaka
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-01-15
Journal Detail:
Title:  The Journal of rheumatology     Volume:  37     ISSN:  0315-162X     ISO Abbreviation:  J. Rheumatol.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-03-03     Completed Date:  2010-05-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7501984     Medline TA:  J Rheumatol     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  512-20     Citation Subset:  IM    
Affiliation:
First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.
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MeSH Terms
Descriptor/Qualifier:
Aged
Arthritis, Rheumatoid / drug therapy*,  metabolism,  pathology
CD4-Positive T-Lymphocytes / drug effects*,  pathology
Calcineurin / antagonists & inhibitors*
Case-Control Studies
Drug Resistance / drug effects
Female
Follow-Up Studies
Humans
Immunosuppressive Agents / pharmacology,  therapeutic use
Male
Middle Aged
P-Glycoprotein / antagonists & inhibitors*,  genetics,  metabolism
Tacrolimus / pharmacology,  therapeutic use*
Treatment Outcome
Chemical
Reg. No./Substance:
0/Immunosuppressive Agents; 0/P-Glycoprotein; 109581-93-3/Tacrolimus; EC 3.1.3.16/Calcineurin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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