Role of FK506 Binding Protein on Tacrolimus Distribution in Red Blood Cells
- PDF / 771,726 Bytes
- 8 Pages / 595.276 x 790.866 pts Page_size
- 49 Downloads / 156 Views
RESEARCH PAPER
Role of FK506 Binding Protein on Tacrolimus Distribution in Red Blood Cells Naoki Yoshikawa 1 Ryuji Ikeda 1
1
2
2
1
& Tsubasa Yokota & Ayako Matsuo & Nobuhiro Matsumoto & Tomomi Iwakiri &
Received: 10 February 2020 / Accepted: 6 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT 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 concentrationdependent 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 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-02875-z) contains supplementary material, which is available to authorized users. * Naoki Yoshikawa [email protected]
1
Department of Pharmacy, University of Miyazaki Hospital, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan
2
Department of Respiratory Medicine, University of Miyazaki Hospital, Miyazaki, Japan
potential biomarker for predicting the pharmacokinetics and pharmacodynamics of tacrolimus.
KEY WORDS biomarker . distribution . FK506 binding protein . red blood cell . tacrolimus
ABBREVIATIONS ATP DDS FKBP PBS RBC
Adenosine triphosphate Drug delivery system FK506 binding protein Phosphate buffered saline Red blood cell
INTRODUCTION Tacrolimus is a macrolide immunosuppressant isolated from Streptomyces tsukubaensis. Tacrolimus forms complexes with FK506-binding proteins (FKBPs) in the cytoplasm, and its immunosuppressive activity is mediated by complexes formed with the FKBP12 (FKBP1A) isoform. (1,2) Tacrolimus FKBP12 complex binds to and inhibits the activity of calcineurin. This causes downregulation of signal transduction pathways in T cells. (1,2) Via the inhibition of calcineurin, tacrolimus interferes with the translocation of various nuclear factors involved in cytokine transcription to the nucleus. (1,2) The pharmacokinetics of ta
Data Loading...
