Role of FK506 Binding Protein on Tacrolimus Distribution in Red Blood Cells
Role of FK506 Binding Protein on Tacrolimus Distribution in Red Blood Cells
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DOI：
10.1007/s11095-020-02875-z
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发表时间：
2020-07-13
影响因子：
3.7
通讯作者：
Ikeda, Ryuji
中科院分区：
文献类型：
--
作者：
Yoshikawa, Naoki;Yokota, Tsubasa;Ikeda, Ryuji
目的他克莫司进入血液后主要分布在红细胞中。本研究旨在评估FK506结合蛋白（FKBPs）对他克莫司在生理environment.MethodsHuman红细胞分布的影响，从健康志愿者的新鲜血液样品中分离。体外研究FKBPs对他克莫司红细胞分布各过程的影响。通过雷帕霉素的抑制实验评估细胞内FKBPs的作用，雷帕霉素竞争性抑制他克莫司与FKBPs的结合。细胞外FKBPs的影响进行了检查，通过预暴露的红细胞FKBP和预孵育的他克莫司与FKBP.ResultsPretreatment与雷帕霉素显着降低率的他克莫司在红细胞中的分布在浓度依赖性的方式。将RBC预先暴露于FKBP12，然后暴露于他克莫司，以浓度依赖性方式显著降低他克莫司在RBC中的分布。此外，他克莫司与FKBP 12的预孵育显着降低他克莫司在RBC中的分布率。结论FKBP在他克莫司在RBC中的分布发挥了重要作用。细胞内和细胞外FKBP对他克莫司在循环血液中的RBC分布的影响是显著的。FKBP是预测他克莫司药代动力学和药效学的潜在生物标志物。
PurposeTacrolimus is distributed mainly in red blood cells (RBCs) after transfer into blood. This study aimed to evaluate the effect of FK506-binding proteins (FKBPs) on RBC distribution of tacrolimus in a physiological environment.MethodsHuman RBCs were isolated from fresh blood samples from healthy volunteers. The effect of FKBPs on each process of the RBC distribution of tacrolimus was evaluated in vitro. Effect of intracellular FKBPs was assessed by inhibition experiment with rapamycin, which competitively inhibits the binding of tacrolimus to FKBPs. Effect of extracellular FKBPs was examined by pre-exposure of RBCs to FKBP and preincubation of tacrolimus with FKBP.ResultsPretreatment with rapamycin significantly reduced the rate of tacrolimus distribution in RBCs in a concentration-dependent manner. Pre-exposure of RBCs to FKBP12 followed by exposure to tacrolimus significantly decreased tacrolimus distribution in RBCs in a concentration-dependent manner. In addition, preincubation of tacrolimus with FKBP12 significantly reduced the rate of tacrolimus distribution in RBCs.ConclusionsFKBP played an important role in the distribution of tacrolimus in RBCs. The effect of intracellular and extracellular FKBPs on RBC distribution of tacrolimus in circulating blood was substantial. FKBP was shown as a potential biomarker for predicting the pharmacokinetics and pharmacodynamics of tacrolimus.