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
复制标题
DOI：
10.1007/s10165-009-0247-0
复制
发表时间：
2010-04-01
影响因子：
2.2
通讯作者：
Tanaka, Yoshiya
中科院分区：
文献类型：
--
作者：
Tsujimura, Shizuyo;Saito, Kazuyoshi;Tanaka, Yoshiya
活化淋巴细胞上的P-糖蛋白（P-gp）是一种三磷酸腺苷（ATP）结合盒转运蛋白，通过排斥活动性类风湿关节炎（RA）患者的细胞内药物而导致耐药性。然而，英夫利西单抗与甲氨蝶呤（MTX）可以克服P-gp介导的耐药性。我们遇到不能继续英夫利西单抗或MTX的患者。在这里，我们测试了依那西普如何影响P-gp介导的耐药性在这样的难治性RA患者。11例RA患者（3例从英夫利西单抗转换，8例不能用MTX治疗）的外周淋巴细胞通过流式细胞术分析P-gp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患者活化的淋巴细胞过度表达P-gp，共表达CD 69。这些淋巴细胞与地塞米松在体外孵育可降低细胞内地塞米松水平。两周依那西普治疗显著降低了P-gp表达，消除了P-gp和CD 69高表达亚组。P-gp的减少导致淋巴细胞中细胞内地塞米松水平的恢复和疾病活动的改善，从而允许皮质类固醇的减量。所有患者均未出现任何严重不良反应。依那西普可用于克服P-gp介导的难治性RA患者的治疗耐药性，这些患者必须停用英夫利西单抗或对MTX不耐受。
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.