Methotrexate Reduces the Clearance of Adalimumab by Increasing the Concentration of Neonatal Fc Receptor in Tissues
Methotrexate Reduces the Clearance of Adalimumab by Increasing the Concentration of Neonatal Fc Receptor in Tissues
复制标题
甲氨蝶呤通过增加组织中新生儿 Fc 受体的浓度来降低阿达木单抗的清除率
DOI：
10.1007/s11095-019-2696-2
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发表时间：
2019-11-01
影响因子：
3.7
通讯作者：
Cheng, Zeneng
中科院分区：
文献类型：
--
作者：
Deng, Yuwei;Liu, Lixiong;Cheng, Zeneng
目的虽然氨甲喋呤（MTX）与阿达木单抗的药代动力学（PK）相互作用已被发现，但其机制尚不清楚。在这项工作中，MTX对新生儿Fc受体（FcRn）的浓度和MTX和阿达木单抗之间的相互作用的FcRn的作用进行了调查。方法实验在大鼠的FcRn具有正常的生理功能，也在大鼠的FcRn被阻断与FcRn抗体。将大鼠随机分配为每周经口接受安慰剂或0.2 mg/kg MTX，同时腹部皮下注射一次0.5 mg/kg阿达木单抗。比较MTX治疗组和安慰剂组的组织中FcRn浓度和阿达木单抗的PK参数。结果在FcRn功能正常的大鼠中，肝脏中FcRn浓度显著增加，（F= 105.5，p =0.000）和肾脏MTX治疗后，阿达木单抗的清除率（CL/F）相应降低（F= 4.423，p =0.048）。而在注射FcRn抗体的大鼠中，MTX治疗组大鼠肝（F= 1.279，p =0.268）和肾（F= 0.661，p =0.424）组织中FcRn浓度接近安慰剂组。MTX对阿达木单抗的CL/F无影响（F= 0.002，p =0.961）。
PurposeAlthough pharmacokinetic (PK) interaction effects of methotrexate (MTX) on adalimumab have been found, the mechanism of these effects is still unclear. In this work, effects of MTX on the concentration of neonatal Fc receptor (FcRn) and the role of FcRn in the interaction between MTX and adalimumab were investigated.MethodsThe experiment was performed in rats whose FcRn had normal physiological function and also in rats whose FcRn was blocked with FcRn antibody. Rats were randomly assigned to receive placebo or 0.2 mg/kg MTX orally every week while taking one abdominal subcutaneous injection of 0.5 mg/kg adalimumab. The FcRn concentration in tissues and the PK parameters of adalimumab were compared between MTX-treated and placebo groups.ResultsIn rats with normally functioning FcRn, the concentrations of FcRn were significantly increased in the liver (F=105.5,p=0.000) and kidney (F=996.312,p=0.000) after treatment with MTX, and the clearance (CL/F) of adalimumab was decreased accordingly (F=4.423,p=0.048). However, in rats injected with FcRn antibody, the concentrations of FcRn in MTX-treated rats were close to that of the placebo rats in the tissues of the liver (F=1.279,p=0.268) and kidney (F=0.661,p=0.424). The CL/F of adalimumab in rats was also not affected by MTX (F=0.002,p=0.961).ConclusionsFcRn may play a vital role in the interaction between adalimumab and MTX.