Pharmacokinetic and Immunosuppressive Effects of Tacrolimus-Loaded Biodegradable Microspheres

点击翻译按钮获取中文摘要

Objective : To characterize the pharmacokinetics and immunosuppression of a tacrolimus loaded biodegradable microsphere (TLBM) in rats.Methods : We prepared TLBM. DA/Slc rats were given TLBM at a rate of 1.6 mg/kg (n=9), 2.4 mg/kg (n=5), and 7.2 mg/kg (n=7) tacrolimus contents, respectively, by a single subcutaneous administration to achieve sustained release over a long period. DA/Slc rats were given TLBM by a single subcutaneous administration at a rate of 4.8 mg/kg (n=6) tacrolimus contents to clarify the main site of TLBM uptake in the organs. In the rat liver transplantation model, the recipients were given TLBM at a rate of 0.16 mg/kg (n=5), 2.4 mg/kg (n=4), and 4.8 mg/kg (n=3) tacrolimus contents, respectively by a single subcutaneous administration on the first day postoperation. Overall survival days were compared.Results : The mean diameters of TLBM particles were 87-90 μm. The entrapping efficiencies of tacrolimus in two batches of TLBM were 6.48 w/w% and 6.60 w/w%. Continuous flat parallel concentration profiles were significant for 14 days from the first day after a single subcutaneous administration of TLBM (p<0.01). The relationship between the dosages of TLBM administration and area under the concentration-time curve (AUC) up to 18 days demonstrated a linear regression line (p<0.01). Also, the relationship between the dose of TLBM and the survival days of the recipients in the liver transplantation model showed a positive correlation. The present pharmacokinetic study of TLBM revealed significantly increased tacrolimus levels in the regional lymph nodes, compared with other organs except bone marrow (p<0.01).Conclusion : TLBM allowed tacrolimus to release gradually in a very stable manner for 14 days and revealed dose proportionality and dose-dependent immunosuppression after a single subcutaneous administration. The main site of TLBM uptake after subcutaneous administration was the regional lymph node of administration route.