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Polymeric micelles for the solubilization and delivery of cyclosporine A: pharmacokinetics and biodistribution

机译：增溶和递送环孢霉素A的聚合物胶束：药代动力学和生物分布

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The aim of this study was to assess the potential of polymeric micelles to modify the pharmacokinetics and tissue distribution of cyclosporine A (CsA). Drug-loaded methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) micellar solutions in isotonic medium were prepared and administered intravenously to healthy Sprague-Dawley rats. Blood and tissues were harvested and assayed for CsA, and resultant pharmacokinetic parameters and tissue distribution of CsA in its polymeric micellar formulation were compared to its commercially available intravenous formulation (Sandimmune (R)). In the pharmacokinetic assessment, a 6.1 fold increase in the area under the blood concentration versus time curve (AUC) was observed for CsA when given as polymeric micellar formulation as compared to Sandimmune (R). The volume of distribution and clearance of CsA as PEO-b-PCL formulation were observed to be 10.0 and 7.6 fold lower, respectively, compared to the commercial formulation. No significant differences in t(1/2) or MRT could be detected. In the biodistribution study, analysis of tissue samples indicated that the mean AUC of CsA in polymeric micelles was lower in liver, spleen and kidney (1.5, 2.1 and 1.4-fold, respectively). Similar to the pharmacokinetic study in these rats, the polymeric micellar formulation gave rise to 5.7 and 4.9-fold increase in the AUC of CsA in blood and plasma, respectively. Our results show that PEO-b-PCL micelles can effectively solubilize CsA, at the same time confining CsA to the blood circulation and restricting its access to tissues such as kidney, perhaps limiting the onset of toxicity. (c) 2005 Elsevier Ltd. All rights reserved.
机译：这项研究的目的是评估聚合物胶束改变环孢素A（CsA）的药代动力学和组织分布的潜力。在等渗介质中制备载药的甲氧基聚（环氧乙烷）-b-聚（ε-己内酯）（PEO-b-PCL）胶束溶液，并向健康的Sprague-Dawley大鼠静脉内给药。收获血液和组织并测定CsA，并将其聚合物胶束制剂中所得CsA的药代动力学参数和组织分布与其市售静脉内制剂（Sandimmune）进行比较。在药代动力学评估中，当以聚合物胶束制剂形式给药时，与Sandimmune（R）相比，CsA的血药浓度相对时间曲线（AUC）下面积增加了6.1倍。与商业制剂相比，观察到作为PEO-b-PCL制剂的CsA的分布体积和清除率分别低10.0倍和7.6倍。没有检测到t（1/2）或MRT的显着差异。在生物分布研究中，对组织样本的分析表明，聚合物胶束中CsA的平均AUC在肝脏，脾脏和肾脏中较低（分别为1.5倍，2.1倍和1.4倍）。与这些大鼠的药代动力学研究相似，聚合物胶束制剂在血液和血浆中的CsA的AUC分别增加了5.7和4.9倍。我们的结果表明，PEO-b-PCL胶束可有效溶解CsA，同时将CsA限制在血液循环中，并限制其进入肾脏等组织的通道，这可能会限制毒性的发作。 （c）2005 Elsevier Ltd.保留所有权利。

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