Etanercept overcomes P-glycoprotein-induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis
Etanercept overcomes P-glycoprotein-induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis
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DOI：
10.3109/s10165-009-0247-0
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发表时间：
2010-04
影响因子：
2.2
通讯作者：
S. Tsujimura;K. Saito;S. Nakayamada;Yoshiya Tanaka
中科院分区：
文献类型：
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作者：
S. Tsujimura;K. Saito;S. Nakayamada;Yoshiya Tanaka
活化淋巴细胞上的p -糖蛋白（P-gp）是一种与三磷酸腺苷（ATP）结合的卡式转运蛋白，在活动性类风湿关节炎（RA）患者中通过排斥细胞内药物引起耐药性。然而，英夫利昔单抗与甲氨蝶呤（MTX）可以克服p- gp介导的耐药。我们遇到不能继续使用英夫利昔单抗或甲氨蝶呤的患者。在这里，我们测试了依那西普如何影响p- gp介导的顽固性RA患者的耐药。用流式细胞术分析了11例RA患者（3例从英夫利昔单抗切换，8例不能用MTX治疗）外周血淋巴细胞P-gp的表达，并使用放射性同位素标记的地塞米松进行药物排除。RA患者活化淋巴细胞过表达P-gp和共表达CD69。用地塞米松体外培养这些淋巴细胞可降低细胞内地塞米松水平。为期两周的依那西普治疗可显著降低P-gp表达，消除P-gp和cd69高表达亚组。P-gp的减少导致淋巴细胞内地塞米松水平的恢复和疾病活动性的改善，从而允许逐渐减少皮质类固醇。所有患者均未出现严重的不良反应。依那西普对于必须停止英夫利昔单抗或甲氨蝶呤不耐受的难治性RA患者克服p- gp介导的治疗耐药是有用的。
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.