New strategy of tacrolimus administration in animal model based on tacrolimus-loaded microspheres.
New strategies for tacrolimus administration that conserve its immunosuppressive effect but avoiding fluctuations in tacrolimus circulating levels are needed. The aim was to analyze if subcutaneous biodegradable tacrolimus-loaded microspheres injection promoted a significant immunosuppressive response in rats. Rats received two subcutaneous tacrolimus-loaded microspheres injections at different days, the first injection was done at day 0 and the second injection was done 12 days after. Plasma circulating levels of tacrolimus, interleukin-2 (IL-2) and calcineurin phosphatase (PP2B) activity in mononuclear cells were measured. Tacrolimus plasma levels were significantly increased from the day after tacrolimus-loaded microspheres injection and remained increased during 10days. Compared to control, plasma IL-2 levels and PP2B activity in mononuclear cells were significantly decreased during ten days. At day 12, a new subcutaneous injection of tacrolimus-loaded microspheres was performed and two days after injection, tacrolimus plasma levels were again increased and both IL-2 plasma levels and PP2B activity decreased. A single subcutaneous tacrolimus-loaded microspheres injection was enough to reduce tacrolimus-related immunosuppressive parameters. These results open the possibility of new therapeutic strategies to administrate calcineurin inhibitors reducing the variability of their circulating levels related to gastrointestinal drug absorption/metabolism modifications.
Medicine Department of the School of Medicine, Universidad Complutense de Madrid, Spain.
Jose J
JJ
Zamorano-Leon
Biochemistry Department of the School of Medicine, Molecular Biology, Universidad Complutense de Madrid, Spain.
Ines
I
Hernandez-Fisac
Biochemistry Department of the School of Medicine, Molecular Biology, Universidad Complutense de Madrid, Spain.
Sandra
S
Guerrero
Biochemistry Department of the School of Medicine, Molecular Biology, Universidad Complutense de Madrid, Spain.
Jorge
J
Tamarit-Rodriguez
Preventive Medicine and Public Health Departments of the School of Medicine, Universidad Complutense de Madrid, Spain.
Juana M
JM
Santos-Sancho
Medicine Department of the School of Medicine, Universidad Complutense de Madrid, Spain.
Bernardo
B
Sopeña
Department of Hemotherapy-Hemostasis, Hospital Clinic, Centre de Diagnostic Biomedic, Institut d'Investigacions Biomediques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
Ginés
G
Escolar
Department of Hemotherapy-Hemostasis, Hospital Clinic, Centre de Diagnostic Biomedic, Institut d'Investigacions Biomediques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
Irene
I
López-Vilchez
Department of Pharmacology, University of Granada, Spain.
Juan
J
Duarte
Medicine Department of the School of Medicine, Universidad Complutense de Madrid, Spain.
Alberto
A
Barrientos
Medicine Department of the School of Medicine, Universidad Complutense de Madrid, Spain. Electronic address: ajlf@telefonica.net.
Antonio J
AJ
López-Farré
D000818:Animals; D016503:Drug Delivery Systems; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D008297:Male; D008863:Microspheres; D023421:Models, Animal; D016377:Organ Transplantation; D051381:Rats; D011921:Rats, Inbred WKY; D016559:Tacrolimus / Q000627:therapeutic use*; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D016559:Tacrolimus
Biodegradable microspheres; Calcineurin phosphatase; Interleukin-2; Rats and tacrolimus