Pharmacokinetic and Immunosuppressive Effects of Tacrolimus-Loaded Biodegradable Microspheres

目的：目的：研究他克莫司生物可降解微球（TLBM）在大鼠体内的药代动力学和免疫抑制作用。通过单次皮下给药，分别以1.6 mg/kg（n=9）、2.4 mg/kg（n=5）和7.2 mg/kg（n=7）他克莫司含量的速率给予DA/Slc大鼠TLBM，以实现长期持续释放。以4.8 mg/kg（n=6）他克莫司含量的速率通过单次皮下给药给予DA/Slc大鼠TLBM，以阐明器官中TLBM摄取的主要部位。在大鼠肝移植模型中，受体在术后第一天皮下分别给予0.16 mg/kg（n=5）、2.4 mg/kg（n=4）和4.8 mg/kg（n=3）他克莫司含量的TLBM。结果：TLBM颗粒平均直径为87-90 μm。两批TLBM中他克莫司的包封率分别为6.48 w/w%和6.60 w/w%。从TLBM单次皮下给药后第一天开始，连续平坦平行浓度曲线在14天内是显著的（p<0.01）。TLBM给药剂量与浓度-时间曲线下面积（AUC）之间的关系长达18天，显示线性回归线（p<0.01）。TLBM剂量与肝移植受者存活时间呈正相关。结论：TLBM可使他克莫司在局部淋巴结中以非常稳定的方式逐渐释放14 d，并显示剂量比例性和剂量依赖性免疫抑制作用。皮下给药后TLBM摄取的主要部位是给药途径的区域淋巴结。

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.