Research Institute of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China.
Department of Rheumatology, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, China.
Pharm Res. 2019 Sep 6;36(11):157. doi: 10.1007/s11095-019-2696-2.
Although 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.
The 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.
In 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).
FcRn may play a vital role in the interaction between adalimumab and MTX.
尽管已经发现甲氨蝶呤（MTX）对阿达木单抗的药代动力学（PK）相互作用，但这些作用的机制仍不清楚。在这项工作中，研究了 MTX 对新生 Fc 受体（FcRn）浓度的影响以及 FcRn 在 MTX 与阿达木单抗相互作用中的作用。
该实验在 FcRn 具有正常生理功能的大鼠和 FcRn 被 FcRn 抗体阻断的大鼠中进行。大鼠随机分为每周口服 0.2mg/kg MTX 组或安慰剂组，同时每周接受一次 0.5mg/kg 阿达木单抗的腹腔皮下注射。比较 MTX 治疗组和安慰剂组组织中 FcRn 浓度和阿达木单抗 PK 参数。
在 FcRn 正常功能的大鼠中，MTX 治疗后肝（F=105.5，p=0.000）和肾（F=996.312，p=0.000）中 FcRn 浓度显著升高，阿达木单抗的清除率（CL/F）相应降低（F=4.423，p=0.048）。然而，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 也不影响阿达木单抗的 CL/F（F=0.002，p=0.961）。
FcRn 可能在阿达木单抗与 MTX 相互作用中发挥重要作用。
