New strategy of tacrolimus administration in animal model based on tacrolimus-loaded microspheres
Graphical abstract
Introduction
Tacrolimus (FK506, Prograf) is a macrolide immunosuppressant agent indicated for the prophylaxis of organ rejection in patients receiving transplantation [1]. Tacrolimus bonds to an immunophilin, FK506 binding protein (FKBP12), forming a complex that inhibits calcineurin phosphatase. Calcineurin phosphatase dephosphorylates the nuclear factors of activated T cells (NFAT), thereby inducing their translocation to the cell nucleus, essential processes for activating cytokine gene expression and, consequently, the immune response [2].
Tacrolimus administration has been associated with severe side effects, including hypertension, nephrotoxicity, and diabetes, that may compromise not only renal graft but also the patients survival [3], [4], [5]. Indeed, tacrolimus nephrotoxicity occurs in 17% to 44% of renal transplant recipients and in 18% to 42% of liver transplant recipients [6], [7].
Despite of the well-established immunosuppressive effects of tacrolimus, its therapeutic use is complicated due to its narrow therapeutic window index [8], [9], [10], [11]. Moreover, tacrolimus shows considerable inter-intra-patient variability in pharmacokinetics profile and a poor oral bioavailability related to its poor solubility [12], [13]. Therefore, guide dose modifications continuous monitoring of circulating levels of tacrolimus is required. In this regard, conventional chronic tacrolimus treatment is based on one or two intakes/daily, as well as an alternative intravenous route indicated for treatment early after transplantation or to cases in which oral route is unavailable. Accordingly, large number of studies has supported that in many patients tacrolimus treatment is subjected to fluctuations in the levels of circulating tacrolimus [8], [10]. The existence of such fluctuations has been attributed to many factors including non-adherence to treatment but also by variability in drug absorption/metabolism [14], [15], [16]. Therefore, new strategies for tacrolimus therapy are obviously needed to obtain prolonged blood tacrolimus concentrations preserving its immunosuppressive effects but avoiding tacrolimus peaks that promote under- and over-tacrolimus dosing.
Biodegradable polymers poly-d,l-lactic-co-glycolic (PLGA) acid has been widely used to form microspheres with capacity to encapsulate drugs allowing continuous long-term delivery of them [17]. The well recognized low toxicity of the polyesters and their degradation products make possible its utilization as a biodegradable drug delivery system without side effects [18], [19]. This microspheres system has been successfully used in treatments of different diseases, avoiding the inconvenient and limitations related to oral chronic treatments [20], [21].
Taken together, the aim of the present study was to analyze if a subcutaneous injection of tacrolimus-loaded microspheres in rats may promote significant immunosuppressive response.
Section snippets
Experimental design
Experiments were completed in male Wistar Kyoto with age range between 12 and 14 weeks with similar body weight (150–200 g). Rats were maintained in temperature-controlled room under 12-hour dark/light cycles and free access to food (standard laboratory chow) and water. All rats received a subcutaneous injection of tacrolimus loaded microspheres that were prepared just before the injection (11.4 mg of tacrolimus loaded microspheres were dispersed in 2 mL of saline solution). Animals were not fasted
Determinations of tacrolimus content
As compared with baseline, tacrolimus plasma levels remained significantly increased from 1 to 10 days after the single subcutaneous injection of tacrolimus-loaded microspheres (Fig. 2). After the single subcutaneous microspheres injection, tacrolimus plasma levels were gradually declined but remained significantly increased with respect to baseline. Tacrolimus reached similar levels to baseline 12 days after tacrolimus-loaded microspheres injection (Fig. 2). Then, at day 12 after the first
Discussion
The present study described a preliminary analyzed new immunosuppressive strategy for tacrolimus administration in rats based on the use of the subcutaneous injection of biodegradable microspheres. Indeed, the results show that a single subcutaneous injection of tacrolimus-loaded microspheres promoted an immunosuppressive response during 10 days after the single injection maintaining increased tacrolimus circulating levels. Moreover, once the immunosuppression response was lost, it was restored
Conflict of interest
The authors declare no conflicts of interest
Acknowledgements
This work was supported by Fondo Investigaciones Sanitarias (FIS) PI09/02163 and Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, Redes Temáticas de Investigación Cooperativa (RETICs) RD12/0042/0040, RD12/0042/0016 and RD12/0042/0011, Fondo Europeo de Desarrollo Regional (Fondos FEDER). We thank Begoña Larrea for editorial assistance and Mª Angeles Rodríguez Alcazar for the technical assistance.
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