Purpose

Tacrolimus 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.

Methods

Human 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.

Results

Pretreatment 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.

Conclusions

FKBP 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.

中文翻译：

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FK506结合蛋白对他克莫司在红细胞中分布的作用。

目的

他克莫司转移到血液后主要分布在红细胞（RBC）中。这项研究旨在评估FK506结合蛋白（FKBPs）对他克莫司在生理环境中RBC分布的影响。

方法

从健康志愿者的新鲜血液样本中分离出人红细胞。体外评估了FKBPs对他克莫司RBC分布的每个过程的影响。通过雷帕霉素的抑制实验评估细胞内FKBPs的作用，雷帕霉素竞争性地抑制他克莫司与FKBPs的结合。通过将RBC预先暴露于FKBP以及他克莫司与FKBP的预孵育来检查细胞外FKBP的作用。

结果

雷帕霉素预处理以浓度依赖性方式显着降低了红细胞中他克莫司的分布速率。将RBC预先暴露于FKBP12，然后再暴露于他克莫司，以浓度依赖的方式显着降低他克莫司在RBC中的分布。此外，他克莫司与FKBP12的预孵育显着降低了他克莫司在RBC中的分布速度。

结论

FKBP在他克莫司在红细胞中的分布中起着重要作用。细胞内和细胞外FKBPs对他克莫司在循环血液中RBC分布的影响很大。FKBP被显示为预测他克莫司药代动力学和药效学的潜在生物标志物。